JP2018511616A - Compositions and methods for modulating short chain dehydrogenase activity - Google Patents

Abstract

Compounds and methods for treating a disease, disorder, or condition where it is desired to modulate 15-PGDH activity, modulate tissue prostaglandin levels, modulate 15-PGDH activity and / or prostaglandin levels 15-PGDH inhibitors described in the literature. [Selection figure] None

Description

RELATED APPLICATION This application claims priority to US Provisional Patent Application No. 62 / 147,305, filed April 14, 2015, the subject matter of which is incorporated herein by reference in its entirety. .

Government funded This invention was made with government support under grant numbers R01CA127306, R01CA127306-03S1, 1P01CA95471-10, AND5P50CA150964 awarded by the National Institutes of Health. The US government may have certain rights to the invention.

  Short chain dehydrogenases (SCDs) are a family of dehydrogenases that share only 15% to 30% sequence identity, and similarities exist primarily in the coenzyme binding domain and the substrate binding domain. In addition to their role in ethanol detoxification, SCD is involved in the synthesis and degradation of fatty acids, steroids, and some prostaglandins, and thus lipid accumulation disease, myopathy, SCD deficiency, and certain heritability Involved in various disabilities such as disabilities.

SCD, 15-hydroxy-prostaglandin dehydrogenase (15-PGDH), (hydroxyprostaglandin dehydrogenase 15- (nicotinamide adenine dinucleotide); 15-PGDH; encoded by enzyme number 1.1.1.141; HPGD gene Catalyzes the inactivation of many active prostaglandins, leukotrienes and hydroxyeicosatetraenoic acid (HETE) (eg, oxidation of PGE ₂ to 15-keto-prostaglandin E2, 15k-PGE) Represents the main enzyme. The human enzyme is encoded by the HPGD gene and is composed of a homodimer with a subunit of 29 kDa size. The enzyme belongs to the evolutionarily conserved superfamily of short chain dehydrogenase / reductase enzymes (SDR), which according to the recently approved nomenclature for human enzymes is named SDR36C1. So far, two forms of 15-PGDH enzyme activity have been identified, NAD + -dependent type I 15-PGDH encoded by the HPGD gene, and type II NADP-dependent 15-, also known as carbonyl reductase 1. PGDH (CBR1, SDR21C1). However, the selectivity of CBR1 for NADP and the high Km value of CBR1 for most prostaglandins suggests that most of the in vivo activity may be due to type I 15-PGDH encoded by the HPGD gene, It is simply designated as 15-PGDH throughout the text below.

Recent studies suggest that inhibitors of 15-PGDH and activators of 15-PGDH can be therapeutically effective. The 15-PGDH knockout mouse model has been shown to increase the incidence of colon tumors. More recent studies have shown increased 15-PGDH expression in the protection of thrombin-mediated cell death. 15-PGDH is well known to be involved in inactivation of prostaglandin E2 (PGE ₂ ), which is a downstream product of COX-2 metabolism. PGE ₂ has been shown to be beneficial in various biological processes such as hair density, skin wound healing, and bone formation.

  Embodiments described herein modulate short chain dehydrogenase (SCD) (eg, 15-PGDH) activity, modulate tissue prostaglandin levels, and / or SCD (eg, 15-PGDH) activity. And / or compounds and methods for treating diseases, disorders, or conditions where it is desired to modulate prostaglandin levels.

式中、ｎ＝０−２であり；
Ｘ^６はＮまたはＣＲ^ｃであり；
Ｒ^１は、−（ＣＨ_２）ｎ_１ＣＨ_３（ｎ_１＝０−７）、

式中、ｎ_２＝０−６であり、Ｘは下記のいずれかである：
ＣＦ_ｙＨ_ｚ（ｙ＋ｚ＝３）、ＣＣｌ_ｙＨ_ｚ（ｙ＋ｚ＝３）、ＯＨ、ＯＡｃ、ＯＭｅ、Ｒ^７１、ＯＲ^７２、ＣＮ、Ｎ（Ｒ^７３）_２、

（ｎ_３＝０−５、ｍ＝１−５）、および

を含む分枝または直鎖アルキルからなる群より選択され；
Ｒ^５は、Ｈ、ＯＨ、Ｃｌ、Ｆ、ＮＨ_２、Ｎ（Ｒ^７６）_２、およびＯＲ^７７からなる群より選択され_；
Ｒ^６およびＲ^７はそれぞれ独立して、下記の１つとすることができ：

各Ｒ^８ _、Ｒ^９ _、Ｒ^１０ _、Ｒ^１１ _、Ｒ^１２ _、Ｒ^１３ _、Ｒ^１４ _、Ｒ^１５ _、Ｒ^１６ _、Ｒ^１７ _、Ｒ^１８ _、Ｒ^１９ _、Ｒ^２０ _、Ｒ^２１ _、Ｒ^２２ _、Ｒ^２３ _、Ｒ^２４ _、Ｒ^２５ _、Ｒ^２６ _、Ｒ^２７ａ _、Ｒ^２７ｂ、Ｒ^２８ _、Ｒ^２９ _、Ｒ^３０ _、Ｒ^３１ _、Ｒ^３２ _、Ｒ^３３ _、Ｒ^３４ _、Ｒ^３５ _、Ｒ^３６ _、Ｒ^３７ _、Ｒ^３８ _、Ｒ^３９ _、Ｒ^４０ _、Ｒ^４１ _、Ｒ^４２ _、Ｒ^４３ _、Ｒ^４４ _、Ｒ^４５ _、Ｒ^４６ _、Ｒ^４７ _、Ｒ^４８ _、Ｒ^４９ _、Ｒ^５０ _、Ｒ^５１ _、Ｒ^５２ _、Ｒ^５３ _、Ｒ^５４ _、Ｒ^５５ _、Ｒ^５６ _、Ｒ^５７ _、Ｒ^５８ _、Ｒ^５９ _、Ｒ^６０ _、Ｒ^６１ _、Ｒ^６２ _、Ｒ^６３ _、Ｒ^６４ _、Ｒ^６５ _、Ｒ^６６ _、Ｒ^６７ _、Ｒ^６８ _、Ｒ^６９ _、Ｒ^７０ _、Ｒ^７１ _、Ｒ^７２ _、Ｒ^７３ _、Ｒ^７４ _、Ｒ^７６、Ｒ^７７、およびＲ^ｃは同じかまたは異なり、かつ、水素、置換もしくは非置換Ｃ_１−Ｃ_２４アルキル、Ｃ_２−Ｃ_２４アルケニル、Ｃ_２−Ｃ_２４アルキニル、Ｃ_３−Ｃ_２０アリール、５−６個の環原子を含むヘテロシクロアルケニル（ここで、１−３個の環原子は、Ｎ、ＮＨ、Ｎ（Ｃ_１−Ｃ_６アルキル）、ＮＣ（Ｏ）（Ｃ_１−Ｃ_６アルキル）、Ｏ、およびＳから独立して選択される）、５−１４個の環原子を含むヘテロアリールまたはヘテロシクリル（ここで、１−６個の環原子は、Ｎ、ＮＨ、Ｎ（Ｃ_１−Ｃ_３アルキル）、Ｏ、およびＳから独立して選択される）、Ｃ_６−Ｃ_２４アルカリル、Ｃ_６−Ｃ_２４アラルキル、ハロ、シリル、ヒドロキシル、スルフヒドリル、Ｃ_１−Ｃ_２４アルコキシ、Ｃ_２−Ｃ_２４アルケニルオキシ、Ｃ_２−Ｃ_２４アルキニルオキシ、Ｃ_５−Ｃ_２０アリールオキシ、アシル（Ｃ_２−Ｃ_２４アルキルカルボニル（−−ＣＯ−アルキル）およびＣ_６−Ｃ_２０アリールカルボニル（−ＣＯ−アリール）を含む）、アシルオキシ（−Ｏ−アシル）、Ｃ_２−Ｃ_２４アルコキシカルボニル（−（ＣＯ）−Ｏ−アルキル）、Ｃ_６−Ｃ_２０アリールオキシカルボニル（−（ＣＯ）−Ｏ−アリール）、Ｃ_２−Ｃ_２４アルキルカルボナト（−Ｏ−（ＣＯ）−Ｏ−アルキル）、Ｃ_６−Ｃ_２０アリールカルボナト（−Ｏ−（ＣＯ）−Ｏ−アリール）、カルボキシ（−ＣＯＯＨ）、カルボキシラト（−ＣＯＯ⁻）、カルバモイル（−（ＣＯ）−−ＮＨ_２）、Ｃ_１−Ｃ_２４アルキル−カルバモイル（−（ＣＯ）−ＮＨ（Ｃ_１−Ｃ_２４アルキル））、アリールカルバモイル（−（ＣＯ）−ＮＨ−アリール）、チオカルバモイル（−（ＣＳ）−ＮＨ_２）、カルバミド（−ＮＨ−（ＣＯ）−ＮＨ_２）、シアノ（−ＣＮ）、イソシアノ（−Ｎ^＋Ｃ⁻）、シアナト（−Ｏ−ＣＮ）、イソシアナト（−Ｏ−Ｎ^＋＝Ｃ⁻）、イソチオシアナト（−Ｓ−ＣＮ）、アジド（−Ｎ＝Ｎ^＋＝Ｎ⁻）、ホルミル（−−（ＣＯ）−−Ｈ）、チオホルミル（−−（ＣＳ）−−Ｈ）、アミノ（−−ＮＨ_２）、Ｃ_１−Ｃ_２４アルキルアミノ、Ｃ_５−Ｃ_２０アリールアミノ、Ｃ_２−Ｃ_２４アルキルアミド（−ＮＨ−（ＣＯ）−アルキル）、Ｃ_６−Ｃ_２０アリールアミド（−ＮＨ−（ＣＯ）−アリール）、スルホンアミド（−ＳＯ_２Ｎ（Ｒ）_２、式中、Ｒは独立してＨ、アルキル、アリールまたはヘテロアリールである）、イミノ（−ＣＲ＝ＮＨ、式中、Ｒは水素、Ｃ_１−Ｃ_２４アルキル、Ｃ_５−Ｃ_２０アリール、Ｃ_６−Ｃ_２４アルカリル、Ｃ_６−Ｃ_２４アラルキル、などである）、アルキルイミノ（−ＣＲ＝Ｎ（アルキル）、式中、Ｒ＝水素、アルキル、アリール、アルカリル、アラルキル、などである）、アリールイミノ（−ＣＲ＝Ｎ（アリール）、式中、Ｒ＝水素、アルキル、アリール、アルカリル、などである）、ニトロ（−ＮＯ_２）、ニトロソ（−ＮＯ）、スルホ（−ＳＯ_２−ＯＨ）、スルホナト（−ＳＯ_２−Ｏ⁻）、Ｃ_１−Ｃ_２４アルキルスルファニル（−Ｓ−アルキル；「アルキルチオ」とも呼ばれる）、アリールスルファニル（−Ｓ−アリール；「アリールチオ」とも呼ばれる）、Ｃ_１−Ｃ_２４アルキルスルフィニル（−（ＳＯ）−アルキル）、Ｃ_５−Ｃ_２０アリールスルフィニル（−（ＳＯ）−アリール）、Ｃ_１−Ｃ_２４アルキルスルホニル（−ＳＯ_２−アルキル）、Ｃ_５−Ｃ_２０アリールスルホニル（−ＳＯ_２−アリール）、スルホンアミド（−ＳＯ_２−ＮＨ_２、−ＳＯ_２ＮＹ_２（式中、Ｙは独立してＨ、アリーリル（ａｒｌｙｌ）またはアルキルである）、ホスホノ（−Ｐ（Ｏ）（ＯＨ）_２）、ホスホナト（−Ｐ（Ｏ）（Ｏ⁻）_２）、ホスフィナト（−Ｐ（Ｏ）（Ｏ⁻））、ホスホ（−ＰＯ_２）、ホスフィノ（−−ＰＨ_２）、ポリアルキルエーテル（−［（ＣＨ_２）_ｎＯ］_ｍ）、ホスフェート、リン酸エステル［−ＯＰ（Ｏ）（ＯＲ）_２、式中、Ｒ＝Ｈ、メチルまたは他のアルキルである］、アミノ酸または生理的ｐＨで正または負電荷を有することが予想される他の部分を組み込んだ基、およびそれらの組み合わせからなる群より独立して選択され；
Ｒ^６がＨ、非置換チオフェン、または非置換チアゾールであり、およびＲ^１がブチルである場合、Ｒ^７は、水素ではなく；およびＲ^６がＨ、または非置換フェニル、チオフェン、またはチアゾールであり、およびＲ^１がベンジルまたは（ＣＨ_２）ｎ_５（ＣＨ_３）（ｎ_５＝０−５）である場合、Ｒ^７は非置換フェニルではない。 In some embodiments, the modulator of SCD can be an SCD inhibitor that can be administered to a tissue or blood of a subject in an amount effective to inhibit the activity of a short chain dehydrogenase enzyme. The SCD inhibitor can be a 15-PGDH inhibitor that can be administered to a tissue or blood of a subject in an amount effective to increase prostaglandin levels in the tissue or blood. The 15-PGDH inhibitor can include a compound having formula (I) as well as a pharmaceutically acceptable salt thereof:

Where n = 0-2;
X ⁶ is N or CR ^c ;
R ¹ is — (CH ₂ ) n ₁ CH ₃ (n ₁ = 0-7),

Where n ₂ = 0-6 and X is one of the following:
CF _y H _z (y + z = 3), CCl _y H _z (y + z = 3), OH, OAc, OMe, R ⁷¹ , OR ⁷² , CN, N (R ⁷³ ) ₂ ,

(N ₃ = 0-5, m = 1-5), and

Selected from the group consisting of branched or straight chain alkyls including:
R ⁵ is selected from the group consisting of H, OH, Cl, F, NH ₂ , N (R ⁷⁶ ) ₂ , and OR ⁷⁷ _;
R ⁶ and R ⁷ can each independently be one of the following:

Each ^{_{R 8, R 9, R 10}} , R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19, R 20, R 21, R 22, R 23, R ^{_{24, R 25, R 26,}} R 27a, R 27b, R 28, R 29, R 30, R 31, R 32, R 33, R 34, R 35, R 36, R 37, R 38, R 39, ^{_{R 40, R 41, R 42}} , R 43, R 44, R 45, R 46, R 47, R 48, R 49, R 50, R 51, R 52, R 53, R 54, R 55, R 56 ^{_{, R 57, R 58, R}} 59, R 60, R 61, R 62, R 63, R 64, R 65, R 66, R 67, R 68, R 69, R 70, R 71, R 72, R ^{7 _{, R 74, R 76, R}} 77, and ^{R c} are the same or different and represent hydrogen, substituted or unsubstituted _C 1 _{-C 24 alkyl,} C 2 _{-C 24 alkenyl,} C 2 _{-C 24} alkynyl, _{C 3} -C ₂₀ aryl, heteroaryl cycloalkenyl containing 5-6 ring atoms (wherein 1-3 ring _{atoms, N, NH, N (C} 1 -C 6 alkyl), NC (O) (C _1- C ₆ alkyl), independently selected from O, and S), heteroaryl or heterocyclyl containing 5-14 ring atoms, wherein 1-6 ring atoms are N, NH, N (C ₁ -C ₃ alkyl), independently selected from O and S), C ₆ -C ₂₄ alkaryl, C ₆ -C ₂₄ aralkyl, halo, silyl, hydroxyl, sulfhydryl, C ₁ -C ₂₄ Alkoxy C ₂ -C _{24 alkenyloxy,} C 2 _{-C 24 alkynyloxy,} C 5 _{-C 20} aryloxy, acyl _(C 2 _{-C 24} alkylcarbonyl (--CO- alkyl) and _C 6 _{-C 20} arylcarbonyl (- including CO- aryl)), acyloxy (-O- _acyl), C 2 _{-C 24} alkoxycarbonyl (- (CO) -O- _alkyl), C 6 _{-C 20} aryloxycarbonyl (- (CO) -O- _aryl), C 2 _{-C 24} alkylcarbonyl diisocyanatohexane (-O- (CO) -O- _alkyl), C 6 _{-C 20} aryl carbonium diisocyanatohexane (-O- (CO) -O- aryl), carboxy (-COOH) , carboxylato (-COO ^-), carbamoyl _{(- (CO) - NH 2} ), C 1 -C 24 alkyl - carbamoyl (- (CO) - H _(C 1 _{-C 24} alkyl)), arylcarbamoyl (- (CO) -NH- aryl), thiocarbamoyl _{(- (CS) -NH 2)} , carbamide _{(-NH- (CO) -NH 2)} , cyano (-CN), isocyano ^(-N + C ^-), cyanato (-O-CN), isocyanato ^{(-O-N + = C -} ), isothiocyanato (-S-CN), azido (-N ^{= N} + ⁼ N ^-), formyl (- (CO) - H) , thioformyl (- (CS) - H) , amino _{(--NH 2), C 1 -C} 24 _alkylamino, C 5 _{-C 20} aryl _amino, C 2 _{-C 24} alkylamido (-NH- (CO) - _alkyl), C 6 _{-C 20} aryl amide (-NH- (CO) - aryl), sulfonamide _{(-SO 2 N (R) 2} , Where R is independently , Alkyl, aryl or heteroaryl), imino (-CR = NH, wherein, R represents _hydrogen, C 1 _{-C 24 alkyl,} C 5 _{-C 20 aryl,} C 6 _{-C 24 alkaryl,} C 6 -C ₂₄ aralkyl, etc.), alkylimino (—CR═N (alkyl), where R = hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (—CR═N (aryl), Wherein R = hydrogen, alkyl, aryl, alkaryl, etc.), nitro (—NO ₂ ), nitroso (—NO), sulfo (—SO ₂ —OH), sulfonate (—SO ₂ —O ⁻ ), C ₁ -C ₂₄ alkylsulfanyl (—S-alkyl; also referred to as “alkylthio”), arylsulfanyl (—S-aryl; also referred to as “arylthio”) _Be), C 1 _{-C 24} alkylsulfinyl (- (SO) - _alkyl), C 5 _{-C 20} arylsulfinyl (- (SO) - _aryl), C 1 _{-C 24} alkylsulfonyl (-SO ₂ - alkyl), C ₅ -C ₂₀ arylsulfonyl (—SO ₂ -aryl), sulfonamide (—SO ₂ —NH ₂ , —SO ₂ NY ₂ , wherein Y is independently H, aryl, or alkyl) , Phosphono (—P (O) (OH) ₂ ), phosphonate (—P (O) (O ⁻ ) ₂ ), phosphinate (—P (O) (O ⁻ )), phospho (—PO ₂ ), phosphino ( --PH _2), polyalkyl ethers _{(- [(CH 2) n} O] m), phosphate, phosphoric acid ester _{[-OP (O) (oR)} 2, where, R = H, methyl or other Is alkyl], selected in an amino acid or physiological pH positive or incorporated group other portions that are expected to have a negative charge, and independently from the group consisting of;
When R ⁶ is H, unsubstituted thiophene, or unsubstituted thiazole, and R ¹ is butyl, R ⁷ is not hydrogen; and R ⁶ is H, or unsubstituted phenyl, thiophene, or thiazole And R ¹ is benzyl or (CH ₂ ) n ₅ (CH ₃ ) (n ₅ = 0-5), then R ⁷ is not unsubstituted phenyl.

In some embodiments, X ⁶ can be N or CH. R ⁶ can be a substituted or unsubstituted heterocyclyl containing 5-6 ring atoms. For example, R ⁶ can be substituted or unsubstituted thiophene, thiazole, oxazole, imidazole, pyridine, or phenyl. R ⁷ is H, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl, alkyl, or carboxy, such as carboxylic acid (—CO ₂ H), carboxy ester (—CO ₂ alkyl) and carboxamide [ -CON (H) may be selected from the group consisting of (alkyl) or _-CO 2 N _{(alkyl) 2].}

式中、ｎ＝０−２であり；
Ｘ^６はＮまたはＣＲ^ｃであり；
Ｘ^７はＮまたはＣであり；
Ｒ^１は、−（ＣＨ_２）ｎ_１ＣＨ_３（ｎ_１＝０−７）、

式中、ｎ_２＝０−６であり、Ｘは下記のいずれかである：
ＣＦ_ｙＨ_ｚ（ｙ＋ｚ＝３）、ＣＣｌ_ｙＨ_ｚ（ｙ＋ｚ＝３）、ＯＨ、ＯＡｃ、ＯＭｅ、Ｒ^７１、ＯＲ^７２、ＣＮ、Ｎ（Ｒ^７３）_２、

を含む分枝または直鎖アルキルからなる群より選択され；
Ｒ^５は、Ｈ、ＯＨ、Ｃｌ、Ｆ、ＮＨ_２、Ｎ（Ｒ^７６）_２、およびＯＲ^７７からなる群より選択され_；
Ｒ^７はそれぞれ独立して、下記の１つとすることができ：

各Ｒ^８ _、Ｒ^９ _、Ｒ^１０ _、Ｒ^１１ _、Ｒ^１２ _、Ｒ^１３ _、Ｒ^１４ _、Ｒ^１５ _、Ｒ^１６ _、Ｒ^１７ _、Ｒ^１８ _、Ｒ^１９ _、Ｒ^２０ _、Ｒ^２１ _、Ｒ^２２ _、Ｒ^２３ _、Ｒ^２４ _、Ｒ^２５ _、Ｒ^２６ _、Ｒ^２７ａ _、Ｒ^２７ｂ _、Ｒ^２８ _、Ｒ^２９ _、Ｒ^３０ _、Ｒ^３１ _、Ｒ^３２ _、Ｒ^３３ _、Ｒ^３４ _、Ｒ^３５ _、Ｒ^３６ _、Ｒ^３７ _、Ｒ^３８ _、Ｒ^３９ _、Ｒ^４０ _、Ｒ^４１ _、Ｒ^４２ _、Ｒ^４３ _、Ｒ^４４ _、Ｒ^４５ _、Ｒ^４６ _、Ｒ^４７ _、Ｒ^４８ _、Ｒ^４９ _、Ｒ^５０ _、Ｒ^５１ _、Ｒ^５２ _、Ｒ^５３ _、Ｒ^５４ _、Ｒ^５５ _、Ｒ^５６ _、Ｒ^５７ _、Ｒ^５８ _、Ｒ^５９ _、Ｒ^６０ _、Ｒ^６１ _、Ｒ^６２ _、Ｒ^６３ _、Ｒ^６４ _、Ｒ^６５ _、Ｒ^６６ _、Ｒ^６７ _、Ｒ^６８ _、Ｒ^６９ _、Ｒ^７０ _、Ｒ^７１ _、Ｒ^７２ _、Ｒ^７３ _、Ｒ^７４ _、Ｒ^７６、Ｒ^７７、Ｒ^ｃ、およびＲ^ｄは同じかまたは異なり、かつ、水素、置換もしくは非置換Ｃ_１−Ｃ_２４アルキル、Ｃ_２−Ｃ_２４アルケニル、Ｃ_２−Ｃ_２４アルキニル、Ｃ_３−Ｃ_２０アリール、５−６個の環原子を含むヘテロシクロアルケニル（ここで、１−３個の環原子は、Ｎ、ＮＨ、Ｎ（Ｃ_１−Ｃ_６アルキル）、ＮＣ（Ｏ）（Ｃ_１−Ｃ_６アルキル）、Ｏ、およびＳから独立して選択される）、５−１４個の環原子を含むヘテロアリールまたはヘテロシクリル（ここで、１−６個の環原子は、Ｎ、ＮＨ、Ｎ（Ｃ_１−Ｃ_３アルキル）、Ｏ、およびＳから独立して選択される）、Ｃ_６−Ｃ_２４アルカリル、Ｃ_６−Ｃ_２４アラルキル、ハロ、シリル、ヒドロキシル、スルフヒドリル、Ｃ_１−Ｃ_２４アルコキシ、Ｃ_２−Ｃ_２４アルケニルオキシ、Ｃ_２−Ｃ_２４アルキニルオキシ、Ｃ_５−Ｃ_２０アリールオキシ、アシル（例えば、Ｃ_２−Ｃ_２４アルキルカルボニル（−−ＣＯ−アルキル）およびＣ_６−Ｃ_２０アリールカルボニル（−ＣＯ−アリール））、アシルオキシ（−Ｏ−アシル）、Ｃ_２−Ｃ_２４アルコキシカルボニル（−（ＣＯ）−Ｏ−アルキル）、Ｃ_６−Ｃ_２０アリールオキシカルボニル（−（ＣＯ）−Ｏ−アリール）、Ｃ_２−Ｃ_２４アルキルカルボナト（−Ｏ−（ＣＯ）−Ｏ−アルキル）、Ｃ_６−Ｃ_２０アリールカルボナト（−Ｏ−（ＣＯ）−Ｏ−アリール）、カルボキシ（−ＣＯＯＨ）、カルボキシラト（−ＣＯＯ⁻）、カルバモイル（−（ＣＯ）−−ＮＨ_２）、Ｃ_１−Ｃ_２４アルキル−カルバモイル（−（ＣＯ）−ＮＨ（Ｃ_１−Ｃ_２４アルキル））、アリールカルバモイル（−（ＣＯ）−ＮＨ−アリール）、チオカルバモイル（−（ＣＳ）−ＮＨ_２）、カルバミド（−ＮＨ−（ＣＯ）−ＮＨ_２）、シアノ（−ＣＮ）、イソシアノ（−Ｎ^＋Ｃ⁻）、シアナト（−Ｏ−ＣＮ）、イソシアナト（−Ｏ−Ｎ^＋＝Ｃ⁻）、イソチオシアナト（−Ｓ−ＣＮ）、アジド（−Ｎ＝Ｎ^＋＝Ｎ⁻）、ホルミル（−−（ＣＯ）−−Ｈ）、チオホルミル（−−（ＣＳ）−−Ｈ）、アミノ（−−ＮＨ_２）、Ｃ_１−Ｃ_２４アルキルアミノ、Ｃ_５−Ｃ_２０アリールアミノ、Ｃ_２−Ｃ_２４アルキルアミド（−ＮＨ−（ＣＯ）−アルキル）、Ｃ_６−Ｃ_２０アリールアミド（−ＮＨ−（ＣＯ）−アリール）、スルホンアミド（−ＳＯ_２Ｎ（Ｒ）_２、式中、Ｒは独立してＨ、アルキル、アリールまたはヘテロアリールである）、イミノ（−ＣＲ＝ＮＨ、ここで、Ｒは水素、Ｃ_１−Ｃ_２４アルキル、Ｃ_５−Ｃ_２０アリール、Ｃ_６−Ｃ_２４アルカリル、Ｃ_６−Ｃ_２４アラルキル、などである）、アルキルイミノ（−ＣＲ＝Ｎ（アルキル）、式中、Ｒ＝水素、アルキル、アリール、アルカリル、アラルキル、などである）、アリールイミノ（−ＣＲ＝Ｎ（アリール）、式中、Ｒ＝水素、アルキル、アリール、アルカリル、などである）、ニトロ（−ＮＯ_２）、ニトロソ（−ＮＯ）、スルホ（−ＳＯ_２−ＯＨ）、スルホナト（−ＳＯ_２−Ｏ⁻）、Ｃ_１−Ｃ_２４アルキルスルファニル（−Ｓ−アルキル；「アルキルチオ」とも呼ばれる）、アリールスルファニル（−Ｓ−アリール；「アリールチオ」とも呼ばれる）、Ｃ_１−Ｃ_２４アルキルスルフィニル（−（ＳＯ）−アルキル）、Ｃ_５−Ｃ_２０アリールスルフィニル（−（ＳＯ）−アリール）、Ｃ_１−Ｃ_２４アルキルスルホニル（−ＳＯ_２−アルキル）、Ｃ_５−Ｃ_２０アリールスルホニル（−ＳＯ_２−アリール）、スルホンアミド（−ＳＯ_２−ＮＨ_２、−ＳＯ_２ＮＹ_２（式中、Ｙは独立してＨ、アリーリル（ａｒｌｙｌ）またはアルキルである）、ホスホノ（−Ｐ（Ｏ）（ＯＨ）_２）、ホスホナト（−Ｐ（Ｏ）（Ｏ⁻）_２）、ホスフィナト（−Ｐ（Ｏ）（Ｏ⁻））、ホスホ（−ＰＯ_２）、ホスフィノ（−−ＰＨ_２）、ポリアルキルエーテル（−［（ＣＨ_２）_ｎＯ］_ｍ）、ホスフェート、リン酸エステル［−ＯＰ（Ｏ）（ＯＲ）_２、式中、Ｒ＝Ｈ、メチルまたは他のアルキルである］、アミノ酸または生理的ｐＨで正または負電荷を有することが予想される他の部分を組み込んだ基、およびそれらの組み合わせからなる群より独立して選択され；
Ｒ^１がブチルである場合、Ｒ^７は水素でなく；およびＲ^１が（ＣＨ_２）ｎ_５（ＣＨ_３）（ｎ_５＝０−５）である場合、Ｒ^７は非置換フェニルではない。 In still other embodiments, the 15-PGDH inhibitor can comprise a compound having formula (II) as well as a pharmaceutically acceptable salt thereof:

Where n = 0-2;
X ⁶ is N or CR ^c ;
X ⁷ is N or C;
R ¹ is — (CH ₂ ) n ₁ CH ₃ (n ₁ = 0-7),

Where n ₂ = 0-6 and X is one of the following:
CF _y H _z (y + z = 3), CCl _y H _z (y + z = 3), OH, OAc, OMe, R ⁷¹ , OR ⁷² , CN, N (R ⁷³ ) ₂ ,

Selected from the group consisting of branched or straight chain alkyls including:
R ⁵ is selected from the group consisting of H, OH, Cl, F, NH ₂ , N (R ⁷⁶ ) ₂ , and OR ⁷⁷ _;
Each R ⁷ can independently be one of the following:

Each ^{_{R 8, R 9, R 10}} , R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19, R 20, R 21, R 22, R 23, R ^{_{24, R 25, R 26,}} R 27a, R 27b, R 28, R 29, R 30, R 31, R 32, R 33, R 34, R 35, R 36, R 37, R 38, R 39, ^{_{R 40, R 41, R 42}} , R 43, R 44, R 45, R 46, R 47, R 48, R 49, R 50, R 51, R 52, R 53, R 54, R 55, R 56 ^{_{, R 57, R 58, R}} 59, R 60, R 61, R 62, R 63, R 64, R 65, R 66, R 67, R 68, R 69, R 70, R 71, R 72, R ^{7 3} _, R ⁷⁴ _, R ⁷⁶ , R ⁷⁷ , R ^c , and R ^d are the same or different and are hydrogen, substituted or unsubstituted C ₁ -C ₂₄ alkyl, C ₂ -C ₂₄ alkenyl, C ₂ -C _{24 alkynyl,} C 3 _{-C 20} aryl, heteroaryl cycloalkenyl containing 5-6 ring atoms (wherein 1-3 ring _{atoms, N, NH, N (C} 1 -C 6 alkyl), NC ( O) (C ₁ -C ₆ alkyl), independently selected from O and S), heteroaryl or heterocyclyl containing 5-14 ring atoms, wherein 1-6 ring atoms are N, NH, N (C ₁ -C ₃ alkyl), O, and S independently selected), C ₆ -C ₂₄ alkaryl, C ₆ -C ₂₄ aralkyl, halo, silyl, hydroxyl, sulfhydryl, C ₁ -C ₂₄ A _Kokishi, C 2 _{-C 24 alkenyloxy,} C 2 _{-C 24 alkynyloxy,} C 5 _{-C 20} aryloxy, acyl _(e.g., C 2 _{-C 24} alkylcarbonyl (--CO- alkyl) and _C 6 _{-C 20} arylcarbonyl (-CO- aryl)), acyloxy (-O- _acyl), C 2 _{-C 24} alkoxycarbonyl (- (CO) -O- _alkyl), C 6 _{-C 20} aryloxycarbonyl (- (CO) - O- _aryl), C 2 _{-C 24} alkylcarbonyl diisocyanatohexane (-O- (CO) -O- _alkyl), C 6 _{-C 20} aryl carbonium diisocyanatohexane (-O- (CO) -O- aryl), carboxy (- COOH), carboxylato (-COO ^-), carbamoyl _{(- (CO) - NH 2} ), C 1 -C 24 alkyl - carbamoyl (- CO) _-NH (C 1 _{-C 24} alkyl)), arylcarbamoyl (- (CO) -NH- aryl), thiocarbamoyl _{(- (CS) -NH 2)} , carbamide (-NH- (CO) -NH ₂ ), Cyano (—CN), isocyano (—N ⁺ C ⁻ ), cyanato (—O—CN), isocyanato (—O—N ⁺ = C ⁻ ), isothiocyanato (—S—CN), azide (—N═ N ⁺ = N ^-), formyl (- (CO) - H) , thioformyl (- (CS) - H) , amino _{(--NH 2), C 1 -C} 24 alkylamino, _{C 5} - C _{20 arylamino,} C 2 _{-C 24} alkylamido (-NH- (CO) - _alkyl), C 6 _{-C 20} aryl amide (-NH- (CO) - aryl), sulfonamide _(-SO 2 N (R ) _2, wherein, R Independently is H, alkyl, aryl or heteroaryl), imino (-CR = NH, wherein, R represents _hydrogen, C 1 _{-C 24 alkyl,} C 5 _{-C 20 aryl,} C 6 _{-C 24} alkaryl, C ₆ -C ₂₄ aralkyl, etc.), alkylimino (—CR═N (alkyl), where R = hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (—CR═N (Aryl), where R = hydrogen, alkyl, aryl, alkaryl, etc.), nitro (—NO ₂ ), nitroso (—NO), sulfo (—SO ₂ —OH), sulfonate (—SO ₂ —) O ⁻ ), C ₁ -C ₂₄ alkylsulfanyl (—S-alkyl; also referred to as “alkylthio”), arylsulfanyl (—S-aryl; “arylthio” Also called O _"), C 1 _{-C 24} alkylsulfinyl (- (SO) - _alkyl), C 5 _{-C 20} arylsulfinyl (- (SO) - _aryl), C 1 _{-C 24} alkylsulfonyl (-SO ₂ - Alkyl), C ₅ -C ₂₀ arylsulfonyl (—SO ₂ -aryl), sulfonamide (—SO ₂ —NH ₂ , —SO ₂ NY ₂ , wherein Y is independently H, aryl, or alkyl ), Phosphono (—P (O) (OH) ₂ ), phosphonate (—P (O) (O ⁻ ) ₂ ), phosphinate (—P (O) (O ⁻ )), phospho (—PO ₂ ) , phosphino (--PH _2), polyalkyl ethers _{(- [(CH 2) n} O] m), phosphate, phosphoric acid ester _{[-OP (O) (OR)} 2, where, R = H, methylcarbamoyl Or other alkyl, selected amino acid or physiological pH positive or incorporated group other portions that are expected to have a negative charge, and independently from the group consisting of;
When R ¹ is butyl, R ⁷ is not hydrogen; and when R ¹ is (CH ₂ ) n ₅ (CH ₃ ) (n ₅ = 0-5), R ⁷ is not unsubstituted phenyl.

式中、ｎ＝０−２であり；
Ｘ^６はＮまたはＣＲ^ｃであり；
Ｘ^７はＮまたはＣであり；
Ｒ^１は、−（ＣＨ_２）ｎ_１ＣＨ_３（ｎ_１＝０−７）、

式中、ｎ_２＝０−６であり、Ｘは下記のいずれかである：
ＣＦ_ｙＨ_ｚ（ｙ＋ｚ＝３）、ＣＣｌ_ｙＨ_ｚ（ｙ＋ｚ＝３）、ＯＨ、ＯＡｃ、ＯＭｅ、Ｒ^７１、ＯＲ^７２、ＣＮ、Ｎ（Ｒ^７３）_２、

を含む分枝または直鎖アルキルからなる群より選択され；
Ｒ^５は、Ｈ、ＯＨ、Ｃｌ、Ｆ、ＮＨ_２、Ｎ（Ｒ^７６）_２、およびＯＲ^７７からなる群より選択され；
Ｒ^７は各々独立して、下記の１つを含む５員複素環とすることができ：

各Ｒ^８ _、Ｒ^９ _、Ｒ^１０ _、Ｒ^１１ _、Ｒ^１２ _、Ｒ^１３ _、Ｒ^１４ _、Ｒ^１５ _、Ｒ^１６ _、Ｒ^１７ _、Ｒ^１８ _、Ｒ^１９ _、Ｒ^２０ _、Ｒ^２１ _、Ｒ^２２ _、Ｒ^２３ _、Ｒ^２４ _、Ｒ^２５ _、Ｒ^２６ _、Ｒ^２７ａ _、Ｒ^２７ｂ _、Ｒ^２８ _、Ｒ^２９ _、Ｒ^３０ _、Ｒ^３１ _、Ｒ^３２ _、Ｒ^３３ _、Ｒ^３４ _、Ｒ^３５ _、Ｒ^３６ _、Ｒ^３７ _、Ｒ^３８ _、Ｒ^３９ _、Ｒ^４０ _、Ｒ^４１ _、Ｒ^４２ _、Ｒ^４３ _、Ｒ^４４ _、Ｒ^４５ _、Ｒ^４６ _、Ｒ^４７ _、Ｒ^７１ _、Ｒ^７２ _、Ｒ^７３ _、Ｒ^７４ _、Ｒ^７６、Ｒ^７７、Ｒ^ｃ、およびＲ^ｄは同じかまたは異なり、かつ、水素、置換もしくは非置換Ｃ_１−Ｃ_２４アルキル、Ｃ_２−Ｃ_２４アルケニル、Ｃ_２−Ｃ_２４アルキニル、Ｃ_３−Ｃ_２０アリール、５−６個の環原子を含むヘテロシクロアルケニル（ここで、１−３個の環原子は、Ｎ、ＮＨ、Ｎ（Ｃ_１−Ｃ_６アルキル）、ＮＣ（Ｏ）（Ｃ_１−Ｃ_６アルキル）、Ｏ、およびＳから独立して選択される）、５−１４個の環原子を含むヘテロアリールまたはヘテロシクリル（ここで、１−６個の環原子は、Ｎ、ＮＨ、Ｎ（Ｃ_１−Ｃ_３アルキル）、Ｏ、およびＳから独立して選択される）、Ｃ_６−Ｃ_２４アルカリル、Ｃ_６−Ｃ_２４アラルキル、ハロ、シリル、ヒドロキシル、スルフヒドリル、Ｃ_１−Ｃ_２４アルコキシ、Ｃ_２−Ｃ_２４アルケニルオキシ、Ｃ_２−Ｃ_２４アルキニルオキシ、Ｃ_５−Ｃ_２０アリールオキシ、アシル（例えば、Ｃ_２−Ｃ_２４アルキルカルボニル（−−ＣＯ−アルキル）およびＣ_６−Ｃ_２０アリールカルボニル（−ＣＯ−アリール））、アシルオキシ（−Ｏ−アシル）、Ｃ_２−Ｃ_２４アルコキシカルボニル（−（ＣＯ）−Ｏ−アルキル）、Ｃ_６−Ｃ_２０アリールオキシカルボニル（−（ＣＯ）−Ｏ−アリール）、Ｃ_２−Ｃ_２４アルキルカルボナト（−Ｏ−（ＣＯ）−Ｏ−アルキル）、Ｃ_６−Ｃ_２０アリールカルボナト（−Ｏ−（ＣＯ）−Ｏ−アリール）、カルボキシ（−ＣＯＯＨ）、カルボキシラト（−ＣＯＯ⁻）、カルバモイル（−（ＣＯ）−−ＮＨ_２）、Ｃ_１−Ｃ_２４アルキル−カルバモイル（−（ＣＯ）−ＮＨ（Ｃ_１−Ｃ_２４アルキル））、アリールカルバモイル（−（ＣＯ）−ＮＨ−アリール）、チオカルバモイル（−（ＣＳ）−ＮＨ_２）、カルバミド（−ＮＨ−（ＣＯ）−ＮＨ_２）、シアノ（−ＣＮ）、イソシアノ（−Ｎ^＋Ｃ⁻）、シアナト（−Ｏ−ＣＮ）、イソシアナト（−Ｏ−Ｎ^＋＝Ｃ⁻）、イソチオシアナト（−Ｓ−ＣＮ）、アジド（−Ｎ＝Ｎ^＋＝Ｎ⁻）、ホルミル（−−（ＣＯ）−−Ｈ）、チオホルミル（−−（ＣＳ）−−Ｈ）、アミノ（−−ＮＨ_２）、Ｃ_１−Ｃ_２４アルキルアミノ、Ｃ_５−Ｃ_２０アリールアミノ、Ｃ_２−Ｃ_２４アルキルアミド（−ＮＨ−（ＣＯ）−アルキル）、Ｃ_６−Ｃ_２０アリールアミド（−ＮＨ−（ＣＯ）−アリール）、スルホンアミド（−ＳＯ_２Ｎ（Ｒ）_２、式中、Ｒは独立してＨ、アルキル、アリールまたはヘテロアリールである）、イミノ（−ＣＲ＝ＮＨ、式中、Ｒは水素、Ｃ_１−Ｃ_２４アルキル、Ｃ_５−Ｃ_２０アリール、Ｃ_６−Ｃ_２４アルカリル、Ｃ_６−Ｃ_２４アラルキル、などである）、アルキルイミノ（−ＣＲ＝Ｎ（アルキル）、式中、Ｒ＝水素、アルキル、アリール、アルカリル、アラルキル、などである）、アリールイミノ（−ＣＲ＝Ｎ（アリール）、式中、Ｒ＝水素、アルキル、アリール、アルカリル、などである）、ニトロ（−ＮＯ_２）、ニトロソ（−ＮＯ）、スルホ（−ＳＯ_２−ＯＨ）、スルホナト（−ＳＯ_２−Ｏ⁻）、Ｃ_１−Ｃ_２４アルキルスルファニル（−Ｓ−アルキル；「アルキルチオ」とも呼ばれる）、アリールスルファニル（−Ｓ−アリール；「アリールチオ」とも呼ばれる）、Ｃ_１−Ｃ_２４アルキルスルフィニル（−（ＳＯ）−アルキル）、Ｃ_５−Ｃ_２０アリールスルフィニル（−（ＳＯ）−アリール）、Ｃ_１−Ｃ_２４アルキルスルホニル（−ＳＯ_２−アルキル）、Ｃ_５−Ｃ_２０アリールスルホニル（−ＳＯ_２−アリール）、スルホンアミド（−ＳＯ_２−ＮＨ_２、−ＳＯ_２ＮＹ_２（式中、Ｙは独立してＨ、アリーリル（ａｒｌｙｌ）またはアルキルである）、ホスホノ（−Ｐ（Ｏ）（ＯＨ）_２）、ホスホナト（−Ｐ（Ｏ）（Ｏ⁻）_２）、ホスフィナト（−Ｐ（Ｏ）（Ｏ⁻））、ホスホ（−ＰＯ_２）、ホスフィノ（−−ＰＨ_２）、ポリアルキルエーテル（−［（ＣＨ_２）_ｎＯ］_ｍ）、ホスフェート、リン酸エステル［−ＯＰ（Ｏ）（ＯＲ）_２、式中、Ｒ＝Ｈ、メチルまたは他のアルキルである］、アミノ酸または生理的ｐＨで正または負電荷を有することが予想される他の部分を組み込んだ基、およびそれらの組み合わせからなる群より独立して選択され；
Ｒ^７は

ではない。 In still other embodiments, the 15-PGDH inhibitor can include a compound having formula (III) as well as a pharmaceutically acceptable salt thereof:

Where n = 0-2;
X ⁶ is N or CR ^c ;
X ⁷ is N or C;
R ¹ is — (CH ₂ ) n ₁ CH ₃ (n ₁ = 0-7),

Where n ₂ = 0-6 and X is one of the following:
CF _y H _z (y + z = 3), CCl _y H _z (y + z = 3), OH, OAc, OMe, R ⁷¹ , OR ⁷² , CN, N (R ⁷³ ) ₂ ,

Selected from the group consisting of branched or straight chain alkyls including:
R ⁵ is selected from the group consisting of H, OH, Cl, F, NH ₂ , N (R ⁷⁶ ) ₂ , and OR ⁷⁷ ;
Each R ⁷ can independently be a 5-membered heterocycle containing one of the following:

Each ^{_{R 8, R 9, R 10}} , R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19, R 20, R 21, R 22, R 23, R ^{_{24, R 25, R 26,}} R 27a, R 27b, R 28, R 29, R 30, R 31, R 32, R 33, R 34, R 35, R 36, R 37, R 38, R 39, R ⁴⁰ _, R ⁴¹ _, R ⁴² _, R ⁴³ _, R ⁴⁴ _, R ⁴⁵ _, R ⁴⁶ _, R ⁴⁷ _, R ⁷¹ _, R ⁷² _, R ⁷³ _, R ⁷⁴ _, R ⁷⁶ , R ⁷⁷ , R ^c , and R ^d are the same or different, and, Haitai containing hydrogen, substituted or unsubstituted _C 1 _{-C 24 alkyl,} C 2 _{-C 24 alkenyl,} C 2 _{-C 24 alkynyl,} C 3 _{-C 20} aryl, a 5-6 ring atoms Rocycloalkenyl, wherein 1-3 ring atoms are independent of N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O, and S Heteroaryl or heterocyclyl containing 5-14 ring atoms, wherein 1-6 ring atoms are N, NH, N (C ₁ -C ₃ alkyl), O, and S C ₆ -C ₂₄ alkaryl, C ₆ -C ₂₄ aralkyl, halo, silyl, hydroxyl, sulfhydryl, C ₁ -C ₂₄ alkoxy, C ₂ -C ₂₄ alkenyloxy, C ₂ -C _{24 alkynyloxy,} C 5 _{-C 20} aryloxy, acyl _(e.g., C 2 _{-C 24} alkylcarbonyl (--CO- alkyl) and _C 6 _{-C 20} arylcarbonyl (-CO- aryl ), Acyloxy (-O- _acyl), C 2 _{-C 24} alkoxycarbonyl (- (CO) -O- _alkyl), C 6 _{-C 20} aryloxycarbonyl (- (CO) -O- aryl), _{C 2} - C ₂₄ alkyl carbonate (—O— (CO) —O-alkyl), C ₆ -C ₂₀ aryl carbonate (—O— (CO) —O-aryl), carboxy (—COOH), carboxylate (—COO ^-), carbamoyl _{(- (CO) - NH 2} ), C 1 -C 24 alkyl - carbamoyl _{(- (CO) -NH (C} 1 -C 24 alkyl)), arylcarbamoyl (- (CO) -NH- aryl), thiocarbamoyl _{(- (CS) -NH 2)} , carbamide _{(-NH- (CO) -NH 2)} , cyano (-CN), isocyano ^(-N + C ^-), shea Preparative (-O-CN), isocyanato ^{(-O-N + = C -} ), isothiocyanato (-S-CN), azido ^{(-N = N + = N -} ), formyl (- (CO) - H ), thioformyl (- (CS) - H) , amino _{(--NH 2), C 1 -C} 24 _alkylamino, C 5 _{-C 20 arylamino,} C 2 _{-C 24} alkylamido (-NH- ( CO) - _alkyl), C 6 _{-C 20} aryl amide (-NH- (CO) - aryl), sulfonamide _{(-SO 2 N (R) 2} , wherein, R is independently H, alkyl, aryl, or Is heteroaryl), imino (—CR═NH, where R is hydrogen, C ₁ -C ₂₄ alkyl, C ₅ -C ₂₀ aryl, C ₆ -C ₂₄ alkaryl, C ₆ -C ₂₄ aralkyl, etc. ), Alkylimino ( CR = N (alkyl), where R = hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (—CR = N (aryl), where R = hydrogen, alkyl, aryl, alkaryl) ), Nitro (—NO ₂ ), nitroso (—NO), sulfo (—SO ₂ —OH), sulfonate (—SO ₂ —O ⁻ ), C ₁ -C ₂₄ alkylsulfanyl (—S-alkyl). ; also referred to as "alkylthio"), arylsulfanyl (-S- aryl; also termed _"arylthio"), C 1 _{-C 24} alkylsulfinyl (- (SO) - _alkyl), C 5 _{-C 20} arylsulfinyl (- (SO ) - _aryl), C 1 _{-C 24} alkylsulfonyl (-SO ₂ - _alkyl), C 5 _{-C 20} arylsulfonyl ( SO ₂ - aryl), sulfonamide _{(-SO 2 -NH 2, -SO 2} NY 2 ( in the formula, Y is independently H, Aririru (Arlyl) or alkyl), phosphono (-P (O) ( OH) ₂ ), phosphonate (—P (O) (O ⁻ ) ₂ ), phosphinate (—P (O) (O ⁻ )), phospho (—PO ₂ ), phosphino (—PH ₂ ), polyalkyl ether (— [(CH ₂ ) _n O] _m ), phosphate, phosphate ester [—OP (O) (OR) ₂ , where R = H, methyl or other alkyl], amino acid or physiological pH Independently selected from the group consisting of groups incorporating other moieties expected to have a positive or negative charge at and combinations thereof;
R ⁷ is

is not.

In some embodiments, 15-PGDH inhibitors, in recombinant 15-PGDH concentration of about 5nM~ about 10 nM, _{IC 50} of less than 1 [mu] M, preferably _{IC 50} of less than 250 nM, more preferably less than 50 nM IC _50, more preferably _{an IC 50} of less than 10 nM, more preferably with _{an IC 50} of less than 5 nM, can inhibit the enzymatic activity of recombinant 15-PGDH.

  15-PGDH inhibitors are applied to the skin of a subject to promote and / or stimulate skin pigmentation and / or hair growth and / or inhibit hair loss and / or treat skin damage or inflammation Can be provided in a topical composition.

  The 15-PGDH inhibitor can also be administered to a subject to promote wound healing, tissue repair, and / or tissue regeneration and / or tissue graft engraftment or regeneration.

  In one embodiment, the 15-PGDH inhibitor is an oral ulcer, periodontal disease, colitis, ulcerative colitis, gastrointestinal ulcer, inflammatory bowel disease, blood circulation disorder, Raynaud's disease, Buerger's disease, diabetic neuropathy, pulmonary artery The subject can be administered to treat at least one of hypertension, cardiovascular disease, and kidney disease.

  In another embodiment, a 15-PGDH inhibitor can be administered to a subject in combination with a prostanoid agonist for the purpose of enhancing the therapeutic effect of the agonist in a prostaglandin responsive condition.

  In other embodiments, the 15-PGDH inhibitor can be administered to a subject and / or tissue of a subject to increase tissue stem cells. For example, a 15-PGDH inhibitor can be administered to the bone marrow of a subject to increase stem cells in the subject.

  In yet other embodiments, the 15-PGDH inhibitor is used to increase the fitness of donor tissue grafts, donor bone marrow grafts, and / or donor hematopoietic stem cell grafts, tissue graft donors, bone marrow graft donors. And / or hematopoietic stem cell donor, and / or tissue graft, and / or bone marrow graft, and / or hematopoietic stem cell graft. For example, a 15-PGDH inhibitor may be used to increase the fitness of bone marrow as a donor graft to the subject, and / or to the subject's bone marrow, and / or to a subject's hematopoietic stem cell preparation. To increase the fitness of the stem cell preparation as a piece and / or to increase the fitness of the stem cell preparation as a donor graft to the peripheral blood hematopoietic stem cell preparation of the subject and / or the umbilical cord To increase the fitness of stem cell preparations as donor transplants to blood stem cell preparations and / or to reduce the number of cord blood units required for transplantation into cord blood stem cell preparations Can be administered.

  In other embodiments, the 15-PGDH inhibitor mitigates tissue graft rejection, enhances tissue and / or bone marrow graft survival, radiation therapy of the subject or subject's bone marrow, chemotherapy, Or radiation of the bone marrow of a subject or subject to enhance engraftment of progenitor stem cell graft, hematopoietic stem cell graft, or umbilical cord blood stem cell graft to enhance bone marrow graft survival after treatment with immunosuppressive therapy Number of cord blood units required to enhance hematopoietic stem cell graft or umbilical cord stem cell graft survival and / or for transplantation into a subject after treatment with chemotherapy, chemotherapy, or immunosuppressive therapy Can be administered to a subject to reduce.

  In other embodiments, the 15-PGDH inhibitor reduces administration of other treatments or growth factors to recipients of tissue graft transplant, bone marrow transplant, and / or hematopoietic stem cell transplant, or umbilical cord stem cell transplant. Can be administered.

  In some embodiments, the 15-PGDH inhibitor is added to the subject or subject's tissue graft to alleviate graft rejection, enhance graft survival, and / or the subject or subject. It can be administered to enhance graft survival after treatment with radiation therapy, chemotherapy, or immunosuppressive therapy of the bone marrow of the body.

  In other embodiments, the 15-PGDH inhibitor confers resistance to the toxicity or lethal effects of exposure to radiation to the subject or subject's bone marrow, such that the toxic effects of cytoxan, the toxic effects of fludarabine, It can be administered to confer resistance to the toxic effects of chemotherapy, or to the toxic effects of immunosuppressive therapy, to reduce radiation-induced lung toxicity, and / or to reduce infection.

  In yet other embodiments, the 15-PGDH inhibitor increases the number of neutrophils after hematopoietic cell transplantation with bone marrow, hematopoietic stem cells, or umbilical cord blood, so in a subject with neutropia. To increase neutrophil count after chemotherapy or radiation therapy, aplastic anemia, myelodysplasia, myelofibrosis, neutropenia due to other bone marrow diseases, drug-induced neutropenia Neutropenia to increase neutrophil count in subjects with autoimmune neutropenia, idiopathic neutropenia, or neutropenia following viral infection To increase platelet count after transplantation of bone marrow, hematopoietic stem cells, or cord blood with hematopoietic cells to increase neutrophil count in subjects with thrombocytopenia after chemotherapy or radiation therapy Aplastic anemia, myelodysplasia, myelofibrosis, thrombocytopenia due to other bone marrow diseases, drug-induced thrombocytopenia, autoimmune thrombocytopenia, idiopathic To increase platelet count in subjects with thrombocytopenic purpura, idiopathic thrombocytopenia, or thrombocytopenia after viral infection, to increase platelet count in subjects with thrombocytopenia, Red blood cell count, or hematocrit, or hemoglobin in subjects with anemia after chemotherapy or radiation therapy to increase red blood cell count, or hematocrit, or hemoglobin levels after hematopoietic stem cell or hematopoietic cell transplantation with cord blood To increase levels, aplastic anemia, myelodysplasia, myelofibrosis, Increase red blood cell count, or hematocrit, or hemoglobin level count in subjects with anemia of other medulla, drug-induced anemia, immune-mediated anemia, chronic disease anemia, anemia after viral infection, or anemia of unknown cause To increase the number of red blood cells, or hematocrit, or hemoglobin levels in a subject with anemia, to increase bone marrow stem cells after hematopoietic cell transplantation with bone marrow, hematopoietic stem cells, or umbilical cord blood, chemotherapy administration or radiation therapy To increase bone marrow stem cells in later subjects and / or after aplastic anemia, myelodysplasia, myelofibrosis, other disorders of the bone marrow, drug-induced cytopenia, immunocytopenia, after viral infection To increase bone marrow stem cells in a subject with cytopenias or cytopenias For administration to a subject.

  In other embodiments, administration of a 15-PGDH inhibitor can be used to modulate hematopoietic stem cells and hematopoietic development. A 15-PGDH inhibitor increases hematopoietic stem cells and / or neutrophils in a subject's blood, bone marrow, and / or tissue to a subject in need thereof, alone or in combination with a cytokine, and Can be administered to mobilize.

  In some embodiments, administration of a 15-PGDH inhibitor can be combined with G-CSF for the purpose of increasing neutrophils.

  In other embodiments, administration of a 15-PGDH inhibitor can be combined with hematopoietic cytokines for the purpose of increasing neutrophils.

  In yet other embodiments, administration of a 15-PGDH inhibitor can be combined with G-CSF for the purpose of increasing and / or mobilizing peripheral blood hematopoietic stem cells.

  In other embodiments, administration of a 15-PGDH inhibitor can be combined with hematopoietic cytokines for the purpose of increasing and / or mobilizing peripheral blood hematopoietic stem cells.

  In some embodiments, administration of a 15-PGDH inhibitor can be combined with a second agent, eg, prixafor, for the purpose of increasing and / or mobilizing peripheral blood hematopoietic stem cells. .

  In other embodiments, administration of a 15-PGDH inhibitor may increase the number of peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation and / or for the purpose of mobilizing it with G-CSF. Can be combined.

  In yet other embodiments, administration of a 15-PGDH inhibitor is combined with hematopoietic cytokines for the purpose of increasing and / or mobilizing peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation. be able to.

  In other embodiments, administration of a 15-PGDH inhibitor is a second agent for the purpose of increasing and / or mobilizing peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation. Can be combined with, for example, prelixaphor.

  In yet other embodiments, administration of a 15-PGDH inhibitor can be combined with G-CSF for the purpose of increasing the number of hematopoietic stem cells in the blood or bone marrow.

  In other embodiments, administration of a 15-PGDH inhibitor can be combined with hematopoietic cytokines for the purpose of increasing the number of hematopoietic stem cells in the blood or bone marrow.

  In other embodiments, the 15-PGDH inhibitor can be administered to a subject and / or tissue of a subject to increase tissue stem cells. For example, a 15-PGDH inhibitor can be administered to the bone marrow of a subject to increase stem cells in the subject.

  In yet other embodiments, the 15-PGDH inhibitor is used to increase the fitness of donor tissue grafts, donor bone marrow grafts, and / or donor hematopoietic stem cell grafts, tissue graft donors, bone marrow graft donors. And / or hematopoietic stem cell donor, and / or tissue graft, and / or bone marrow graft, and / or hematopoietic stem cell graft. For example, a 15-PGDH inhibitor may be used to increase the fitness of bone marrow as a donor graft to a subject, and / or to the subject's bone marrow, and / or to a subject's hematopoietic stem cell preparation. To increase the fitness of a stem cell preparation as a donor graft and / or to increase the fitness of a stem cell preparation as a donor graft to a subject's peripheral blood hematopoietic stem cell preparation And / or cord blood stem cell preparations to increase the fitness of the stem cell preparations as donor grafts and / or cord blood stem cell preparations of cord blood required for transplantation It can be administered to reduce the number of units.

  In other embodiments, the 15-PGDH inhibitor is used in recipients of tissue graft transplants, bone marrow transplants, and / or hematopoietic stem cell transplants, or umbilical cord stem cell transplants to reduce administration of other treatments or growth factors. Can be administered.

  In yet other embodiments, the 15-PGDH inhibitor increases the number of neutrophils after hematopoietic cell transplantation with bone marrow, hematopoietic stem cells, or umbilical cord blood, so in a subject with neutropia. To increase neutrophil count after chemotherapy or radiation therapy, aplastic anemia, myelodysplasia, myelofibrosis, neutropenia due to other bone marrow diseases, drug-induced neutropenia Neutropenia to increase neutrophil count in subjects with autoimmune neutropenia, idiopathic neutropenia, or neutropenia following viral infection To increase platelet count after transplantation of bone marrow, hematopoietic stem cells, or cord blood with hematopoietic cells to increase neutrophil count in subjects with thrombocytopenia after chemotherapy or radiation therapy Aplastic anemia, myelodysplasia, myelofibrosis, thrombocytopenia due to other bone marrow diseases, drug-induced thrombocytopenia, autoimmune thrombocytopenia, idiopathic To increase platelet count in subjects with thrombocytopenic purpura, idiopathic thrombocytopenia, or thrombocytopenia after viral infection, to increase platelet count in subjects with thrombocytopenia, Red blood cell count, or hematocrit, or hemoglobin in subjects with anemia after chemotherapy or radiation therapy to increase red blood cell count, or hematocrit, or hemoglobin levels after hematopoietic stem cell or hematopoietic cell transplantation with cord blood To increase levels, aplastic anemia, myelodysplasia, myelofibrosis, Increase red blood cell count, or hematocrit, or hemoglobin level count in subjects with anemia of other medulla, drug-induced anemia, immune-mediated anemia, chronic disease anemia, anemia after viral infection, or anemia of unknown cause To increase the number of red blood cells, or hematocrit, or hemoglobin levels in a subject with anemia, to increase bone marrow stem cells after hematopoietic cell transplantation with bone marrow, hematopoietic stem cells, or umbilical cord blood, chemotherapy administration or radiation therapy To increase bone marrow stem cells in later subjects and / or after aplastic anemia, myelodysplasia, myelofibrosis, other disorders of the bone marrow, drug-induced cytopenia, immunocytopenia, after viral infection To increase bone marrow stem cells in a subject with cytopenias or cytopenias For administration to a subject.

  In other embodiments, the 15-PGDH inhibitor can be administered to a subject to increase responsiveness to cytokines in the presence of cytopenia, wherein the cytopenia can be any of the following: Including: neutropenia, thrombocytopenia, lymphopenia and anemia; and cytokines have increased responsiveness enhanced by 15-PGDH inhibitors, including any of the following: G- CSF, GM-CSF, EPO, IL-3, IL-6, TPO, TPO-RA (thrombopoietin receptor agonist), and SCF.

  In some embodiments, the 15-PGDH inhibitor increases bone density, treats osteoporosis, promotes fracture healing, or promotes healing after bone surgery or joint replacement, and / or bone The subject can be administered to promote bone healing for implants, artificial implants, dental implants and transplanted bone.

  In other embodiments, the 15-PGDH inhibitor increases stem cells or cell proliferation in the intestine, and / or is toxic, lethal, due to toxicity or lethal effects of exposure to radiation or treatment with chemotherapy, Or it can be administered to the subject or the intestine of the subject to confer resistance to mucositis effects.

  In some embodiments, the 15-PGDH inhibitor can be administered to the subject or the intestine of the subject as a treatment for colitis, ulcerative colitis, or inflammatory bowel disease.

  In other embodiments, the 15-PGDH inhibitor increases liver regeneration after liver surgery, after living donor liver, after liver transplantation, or after liver damage due to toxins and / or acetaminophen and related compounds. Can be administered to a subject to promote recovery from or resistance to liver toxins.

  In yet other embodiments, the 15-PGDH inhibitor can be administered to a subject to treat erectile dysfunction.

  In still other embodiments, the 15-PGDH inhibitor can be administered to inhibit at least one of the growth, proliferation, or metastasis of a cancer that expresses 15-PGDH.

  Still other embodiments described herein relate to methods of treating a subject in need of cell therapy. The methods are described in preparations comprising human hematopoietic stem cells and / or human hematopoietic stem cells administered with a therapeutically effective amount of a 15-PGDH inhibitor described herein to a subject. Administering a therapeutic composition comprising a 15-PGDH inhibitor.

  In some embodiments, the subject has received human hematopoietic stem cells and / or received a preparation and / or therapeutic composition.

  In other embodiments, the subject has acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), juvenile myelomonocytic leukemia, Hodgkin lymphoma, Non-Hodgkin lymphoma, Multiple myeloma, Severe aplastic anemia, Fanconi anemia, Paroxysmal nocturnal hemoglobinuria (PNH), Erythroblastic fistula, Agronuclear / congenital thrombocytopenia, Severe combined immunity Dysfunction syndrome (SCID), Wiscott-Aldrich syndrome, severe β thalassemia, sickle cell disease, Hurler syndrome, adrenoleukodystrophy, metachromatic leukodystrophy, myelodysplasia, refractory anemia, chronic myelomonocytic leukemia , Primary myelofibrosis, familial erythrocyte phagocytic lymphohistiocytosis, solid tumor, chronic granulomatous disease, mucopolysaccharidosis, or diamo With a de-Blackfan anemia.

  Other embodiments relate to methods of treating a subject having at least one symptom associated with ischemic tissue or tissue damaged by ischemia. The methods are described in preparations comprising human hematopoietic stem cells and / or human hematopoietic stem cells administered with a therapeutically effective amount of a 15-PGDH inhibitor described herein to a subject. Administering a therapeutic composition comprising a 15-PGDH inhibitor.

  In some embodiments, ischemia is acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusion, arteriosclerosis, articular cartilage defect, aseptic Systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, fracture, fracture, cerebral edema, cerebral hypoperfusion, Buerger disease, burn, cancer, cardiovascular disease, cartilage injury, cerebral infarction, cerebral ischemia, stroke , Cerebrovascular disease, chemotherapy-induced neuropathy, chronic infection, chronic mesenteric ischemia, lameness, congestive heart failure, connective tissue injury, contusion, coronary artery disease (CAD), severe ischemic limb (CLI), Crohn's disease, Deep vein thrombosis, deep wound, delayed ulcer healing, delayed wound healing, diabetes (type I and type II), diabetic neuropathy, diabetes-induced ischemia, disseminated intravascular coagulation (DIC), embolic cerebral collapse Blood, graft Host disease, hereditary hemorrhagic telangiectatic ischemic vascular disease, hyperoxia injury, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injured tendon, intermittent claudication, intestinal ischemia, ischemia, imaginary Hematologic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic renal disease, ischemic vascular disease, ischemic-reperfusion injury, laceration, left coronary artery main lesion, ischemic limb, lower limb imagination Blood, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease, peripheral arterial disease (PAD), peripheral arterial disease, peripheral ischemia, peripheral neuropathy, peripheral vascular disease, Precancer, pulmonary edema, pulmonary embolism, remodeling disorder, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcer, solid organ transplantation, spinal cord injury, stroke, subchondral bone cyst, thrombosis, thrombotic brain Ischemia, tissue ischemia, transient ischemic attack (TIA), traumatic brain injury Ulcerative colitis, vascular diseases of the kidney, vascular inflammatory conditions, may at least associated with one of the wounds for von Hippel-Lindau syndrome, and tissue or organ.

  Other embodiments relate to methods for treating and / or preventing fibrosis and various fibrotic diseases, disorders or conditions by administration of a 15-PGDH inhibitor. In some embodiments, the 15-PGDH inhibitors described herein reduce fibrosis symptoms such as collagen deposition, inflammatory cytokine expression, and inflammatory cell infiltration, and in whole or in part, Characterized by overproduction of fibrous material, for example, overproduction of fibrotic material within the extracellular matrix, or abnormal, non-functional and / or excessive accumulation of matrix-related components of normal tissue elements It can be administered to a subject in need thereof to treat and / or prevent various fibrotic diseases, disorders, and conditions attached.

  Fibrous diseases, disorders and conditions characterized in whole or in part by overproduction of fibrotic material include: systemic sclerosis, multifocal fibrosis, renal systemic fibrosis, Scleroderma (including morphea, polymorphism, or linear scleroderma), scleroderma graft-versus-host disease, renal fibrosis (glomerulosclerosis, renal tubular interstitial fibrosis, progressive kidney) Diseases or including diabetic nephropathy), cardiac fibrosis (eg, myocardial fibrosis), pulmonary fibrosis (eg, glomerulosclerosis pulmonary fibrosis, idiopathic pulmonary fibrosis, silicosis, asbestosis, Interstitial lung disease, interstitial fibrosis lung disease, and chemotherapy / radiation-induced lung fibrosis), oral fibrosis, endocardial myocardial fibrosis, deltoid fibrosis, pancreatitis, inflammatory bowel disease, Crohn's disease , Nodular fasciitis scilitis), eosinophilic fasciitis, general fibrosis syndrome characterized by replacement of normal muscle tissue with fibrous tissue at various degrees, retroperitoneal fibrosis, liver fibrosis, cirrhosis, chronic renal failure; myelofibrosis (Myelofibrosis), drug-induced ergot poisoning, glioblastoma, sporadic glioblastoma, myeloid leukemia, acute myeloid leukemia, myelodysplastic syndrome, myeloproliferative in Li-Fraumeni syndrome Syndrome (myeloproliferative syndrome), gynecological cancer, Kaposi's sarcoma, leprosy, collagen colitis, acute fibrosis, organ-specific fibrosis, etc.

  In some embodiments, a method of treating or preventing a disease, disorder or condition comprises administering to a subject in need thereof a therapeutically effective amount of a 15-PGDH inhibitor.

  In some embodiments, 15-PGDH inhibitors can be used to treat or prevent pulmonary fibrosis. The pulmonary fibrosis that can be treated is pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, sarcoidosis, cystic fibrosis, familial pulmonary fibrosis, silicosis , Asbestosis, coal miner pneumoconiosis, carbon pneumoconiosis, hypersensitivity pneumonia, pulmonary fibrosis caused by inhalation of inorganic dust, pulmonary fibrosis caused by infectious agents, harmful gas, aerosol, chemical dust, fume or vapor inhalation The pulmonary fibrosis caused, drug-induced interstitial lung disease, or pulmonary hypertension, and combinations thereof can be selected.

  In other embodiments, 15-PGDH inhibitors can be used to treat or prevent renal fibrosis. Renal fibrosis can result from dialysis after renal failure, catheterization, nephropathy, glomerulosclerosis, glomerulonephritis, chronic renal dysfunction, acute kidney injury, end-stage renal disease or renal failure, or a combination thereof There is sex.

  In other embodiments, 15-PGDH inhibitors can be used to treat or prevent liver fibrosis. Liver fibrosis is chronic liver disease, virus-induced cirrhosis, hepatitis B virus infection, hepatitis C virus infection, hepatitis D virus infection, schistosomiasis, primary biliary cirrhosis, alcoholic liver disease or nonalcoholic Steatohepatitis (NASH), NASH-related cirrhosis obesity, diabetes, protein nutritional disorders, coronary artery disease, autoimmune hepatitis, cystic fibrosis, alpha 1 antitrypsin deficiency, primary biliary cirrhosis, drug reaction and exposure to toxins , Or a combination thereof.

  In some embodiments, 15-PGDH inhibitors can be used to treat or prevent cardiac fibrosis, such as cardiac fibrosis and endocardial myocardial fibrosis.

  In some embodiments, 15-PGDH inhibitors can be used to treat or prevent systemic sclerosis.

  In some embodiments, 15-PGDH inhibitors can be used to treat or prevent a fibrotic disease, disorder or condition caused by post-surgical adhesion formation.

  In some embodiments, 15-PGDH inhibitors can be used to reduce or prevent scar formation in a subject.

  In other embodiments, 15-PGDH inhibitors can be used to reduce or prevent scar formation or scleroderma on the skin.

  In various embodiments, the 15-PGDH inhibitor reduces at least one symptom or characteristic of fibrotic disease, disorder or condition, or other related disease, disorder or condition in intensity, severity, or frequency; Alternatively, it can be administered in a therapeutically effective amount so that onset is delayed.

  In other embodiments, the 15-PGDH inhibitor is used in a method for reducing or reducing collagen secretion or deposition in a tissue or organ of a subject, such as lung, liver, intestine, colon, skin or heart. Can do. The method can include administering a therapeutically effective amount of a 15-PGDH inhibitor to a subject in need thereof. The subject may have or be at risk for excessive collagen secretion or deposition in a tissue or organ, such as the kidney, lung, liver, intestine, colon, skin or heart. Usually, excessive collagen secretion or collagen deposition in organs results from injury or invasion. Such damage or invasion can be organ specific. The 15-PGDH inhibitor can be administered for a period of time sufficient to completely or partially reduce or reduce the level of collagen deposition in a tissue or organ. The sufficient period can be one week, or one week to one month, or one to two months, or more than two months. For chronic conditions, the 15-PGDH inhibitor can be conveniently administered during the lifetime.

  For convenience, certain terms employed in the specification, examples, and appended claims are collected here. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

  The article “a (an)” is used herein to indicate one or more (ie, at least one) of the grammatical objects of the article. By way of example, “an element” means one element or more than one element.

  The terms "include", "include", "contain", "contain", "have" and "have" are used in a comprehensive open sense and may include additional elements Means. The terms “etc.”, “for example” are non-limiting herein and are for illustrative purposes only. “Including” and “including but not limited to” are used interchangeably.

  The term “or” is to be understood herein to mean “and / or” unless the context clearly dictates otherwise.

  As used herein, the term “about” or “approximately” refers to 15%, 10%, 9 with respect to a reference quantity, level, value, number, frequency, percentage, dimension, size, quantity, weight or length. %, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% quantities, quantities, levels, values, numbers, frequencies, percentages, dimensions, sizes, quantities, weights Or length. In one embodiment, the term “about” or “approximately” means ± 15%, ± 10%, for a reference quantity, level, value, number, frequency, percentage, dimension, size, quantity, weight or length, ± 9%, ± 8%, ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, ± 2%, or ± 1% quantities, levels, values, numbers, frequencies, percentages, dimensions Indicates a range of size, quantity, weight or length.

  It will be noted that some structures of the claimed compounds contain asymmetric (chiral) carbon or sulfur atoms. Accordingly, it is to be understood that isomers arising from such asymmetry are included herein unless otherwise indicated. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. The compounds of the present application can exist in stereoisomeric forms and therefore can be produced as individual stereoisomers or as mixtures.

  The term “isomerism” means compounds that have the same molecular formula but differ in nature or the order of bonding of their atoms or the spatial arrangement of their atoms. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". Stereoisomers that are not mirror images of the other are called “diastereoisomers”, and stereoisomers that are non-superimposable mirror images are called “enantiomers”, or sometimes optical isomers. A carbon atom bonded to four nonidentical substituents is referred to as a “chiral center”, and a sulfur, such as sulfoxide or sulfinimide, bonded to three or four different substituents is also referred to as a “chiral center”.

  The term “chiral isomer” means a compound having at least one chiral center. It has two enantiomeric forms of opposite chirality and can exist as individual enantiomers or as a mixture of enantiomers. A mixture containing equal amounts of the opposite enantiomeric forms of the opposite chirality is called a “racemic mixture”. A compound with more than one chiral center has 2n-1 enantiomeric pairs, where n is the number of chiral centers. Compounds having more than one chiral center can exist as individual diastereomers or as a mixture of diastereomers, referred to as “diastereomeric mixtures”. If one chiral center is present, stereoisomers can be characterized by the absolute configuration (R or S) of that chiral center. Alternatively, stereoisomers can be characterized as (+) or (-) when one or more chiral centers are present. Absolute configuration indicates the spatial arrangement of substituents attached to the chiral center. Substituents attached to the chiral center under consideration are ranked according to the Cahn-Ingold-Prelog ranking rule (Cahn et al, Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al. Chem. 1966, 78, 413; Cahn and Ingold, J Chem. Soc. 1951 (London), 612; Cahn et al., Experiatia 1956, 12, C. 81. Cand. 41, 116).

  The term “geometric isomer” means a diastereomer that exists due to rotational hindrance around a double bond. These configurations are distinguished in their names by the prefixes cis and trans, or Z and E, which are functional groups that are the same or opposite of double bonds in the molecule, according to the Kahn-Ingold-Prelog ranking rule. Indicates that it is on the side. Furthermore, the structures and other compounds described in this application include all their atropisomers.

  The term “atropisomer” is a type of stereoisomer in which the atoms of the two isomers are arranged differently in space. Atropisomers exist because of rotation limitations caused by hindering rotation of large groups around the central bond. Such atropisomers typically exist as mixtures, however, as a result of recent advances in chromatographic techniques, in limited cases it is possible to separate a mixture of two atropisomers. It has become.

  The term “crystalline polymorph” or “polymorph” or “crystalline form” means a crystal structure in which a compound (or salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which are Have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal forms, optical and electrical properties, stability and solubility. One crystal form can be governed by recrystallization solvent, crystallization rate, storage temperature, and other factors. Crystal polymorphs of compounds can be prepared by crystallization under different conditions.

  The term “derivative” refers to a compound having a common core structure and substituted with various groups as described herein.

  The term “bioisostere” refers to a compound resulting from the exchange of another or widely similar atom or group of atoms or groups. The purpose of bioequivalence replacement is to create new compounds that have similar biological properties as the parent compound. Bioequivalence replacement may be physicochemical or morphologically based. Examples of carboxylic acid bioisosteres include acylsulfonimide, tetrazole, sulfonate, and phosphonate. See, for example, Patani and LaVoe, Chem. Rev. 96, 3147-3176 (1996).

  The phrases “parenteral administration” and “administered parenterally” are art-recognized terms, including but not limited to modes of administration other than enteral and topical administration, including, but not limited to, Intravenous, intramuscular, intrapleural, intravascular, pericardial, intraarterial, intrathecal, intraarticular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, epidermal, intraarticular, Subcapsular, subarachnoid, intraspinal and intrasternal injections and infusions are included.

  The term “treating” is art-recognized and inhibits a disease, disorder or condition in a subject, eg, prevents its progression; and reduces a disease, disorder or condition, eg , Causing regression of the disease, disorder and / or condition. Treating a disease or condition includes ameliorating at least one symptom of a particular disease or condition, even when the underlying pathophysiology is not affected.

  The term “prevent” is art-recognized and the disease, disorder or condition may be predisposed to the disease, disorder and / or condition but is still diagnosed as having it. Including stopping what happens in non-subject subjects. Preventing a disease state associated with a disease includes stopping the disease state from occurring after the disease is diagnosed but before the disease state is diagnosed.

  The term “pharmaceutical composition” refers to a formulation comprising a disclosed compound in a form suitable for administration to a subject. In preferred embodiments, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form is any of a variety of forms, including capsules, IV bags, tablets, single pumps on aerosol inhalers, or vials. The quantity of active ingredient component (eg, a formulation of a disclosed compound or salt thereof) in a unit dose of the composition is an effective amount and will vary depending on the particular treatment involved. One skilled in the art will recognize that it is sometimes necessary to vary dosages routinely depending on the age and condition of the patient. The dosage will also depend on the route of administration. Various routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, inhalation, and the like. Dosage forms for topical or transdermal administration of the compounds described herein include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, spray compounds, and inhalants. . In a preferred embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants.

  The term “flash dose” refers to a compound formulation that is a rapidly dispersing dosage form.

  The term “immediate release” is defined as the release of a compound from a dosage form over a relatively short period of time, generally up to about 60 minutes. The term “modified release” is defined to include delayed release, sustained release, and pulsed release. The term “pulsed release” is defined as a series of drug releases from a dosage form. The term “sustained release” or “sustained release” is defined as a continuous release of a compound from a dosage form over an extended period of time.

  The phrase “pharmaceutically acceptable” is approved in the art. In certain embodiments, the term is within the scope of sound medical judgment, suitable for use in contact with human and animal tissue, excessive toxicity, irritation, allergic response, or other Including compositions, polymers and other materials and / or dosage forms that are free from the problems or complications of and are commensurate with a reasonable benefit / risk ratio.

  The phrase “pharmaceutically acceptable carrier” is art-recognized and includes, for example, the delivery of any subject composition from one organ or body part to another organ or body part. Or a pharmaceutically acceptable material, composition or vehicle involved in transport, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other material ingredients of the subject composition and not injurious to the patient. In certain embodiments, the pharmaceutically acceptable carrier is non-pyrogenic. Some examples of materials that can function as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; ) Cellulose, and derivatives thereof such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppositories (9) oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol and polyethylene glycol (12) Esters such as ethyl oleate and ethyl laurate; (13) Agar; (14) Buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) Alginic acid; (16) Pyrogen-free water; 17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solution; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

  The compounds of the application can further form salts. All of these forms are also contemplated herein.

  “Pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. For example, the salt can be an acid addition salt. One embodiment of the acid addition salt is the hydrochloride salt. Pharmaceutically acceptable salts can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. In general, such salts are prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two. In general; non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of salts is found in Remington's Pharmaceutical Sciences, 18th Edition (Mack Publishing Company, 1990).

  The compounds described herein can also be prepared as esters, such as pharmaceutically acceptable esters. For example, a carboxylic acid functional group in a compound can be converted to its corresponding ester, eg, methyl, ethyl, or other ester. Also, an alcohol group in a compound can be converted to its corresponding ester, for example, acetic acid, propionic acid, or other ester.

  The compounds described herein can also be prepared as prodrugs, eg, pharmaceutically acceptable prodrugs. The terms “pro-drug” and “prodrug” are used interchangeably herein to indicate any compound that releases an active parent drug in vivo. Since prodrugs are known to enhance many desirable qualities (eg, solubility, bioavailability, manufacturing, etc.) of pharmaceuticals, the compounds can be delivered in prodrug form. Thus, the compounds described herein are intended to include prodrugs of the compounds claimed herein, methods of delivering the same, and compositions comprising the same. “Prodrug” is intended to include any covalently bonded carrier that releases an active parent drug in vivo when such prodrug is administered to a subject. Prodrugs are prepared by modifying functional groups present in the compound such that the modification is cleaved, either routinely or in vivo, to become the parent compound. Prodrugs are those in which a hydroxy, amino, sulfhydryl, carboxy, or carbonyl group is cleaved in vivo to attach to any group that can form a free hydroxyl, free amino, free sulfhydryl, free carboxy or free carbonyl group, respectively. Containing compounds. A prodrug is a precursor (precursor) of a compound described herein that undergoes a chemical transformation by a metabolic process before becoming an active or more active pharmacological agent or active compound described herein. Can be included.

  Examples of prodrugs include, but are not limited to: esters of hydroxy functional groups in compounds (eg, acetic acid, dialkylaminoacetic acid, formic acid, phosphoric acid, sulfuric acid, and benzoic acid derivatives) and carbamates (For example, N, N-dimethylaminocarbonyl), ester group of carboxyl functional group (for example, ethyl ester, morpholinoethanol ester), N-acyl derivative of amino functional group (for example, N-acetyl) N-Mannich base, Schiff Bases and enaminones, oximes, acetals, ketals, and enol esters of ketone and aldehyde functional groups, and the like, and sulfides that are oxidized to form sulfoxides or sulfones.

  The term “protecting group” refers to a population of atoms that when attached to a reactive group in a molecular mask reduces or prevents its reactivity. Examples of protecting groups can be found in: Green and Wuts, Protective Groups in Organic Chemistry, (Wiley, Second Supplement 1991); Harrison and Harrison et al. , Compendium of Synthetic Organic Methods, Vols. 1-8 (John Wiley and Sons, 1971-1996); and Kocienski, Protecting Groups, (Verlag, 3rd edition 2003).

  The term “amine protecting group” can mean a functional group that converts an amine, amide, or other nitrogen-containing moiety to a different chemical group that is substantially inert to the conditions of a particular chemical reaction. Intended. The amine protecting group is preferably removed easily and selectively in good yield under conditions that do not affect other functional groups of the molecule. Examples of amine protecting groups include, but are not limited to: formyl, acetyl, benzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, t-butyloxycarbonyl (Boc), p-methoxybenzyl , Methoxymethyl, tosyl, trifluoroacetyl, trimethylsilyl (TMS), fluorenyl-methyloxycarbonyl, 2-trimethylsilyl-ethyoxycarbonyl, 1-methyl-1- (4-biphenylyl) ethoxycarbonyl, allyloxycarbonyl, benzyl Oxycarbonyl (CBZ), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl groups, 9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarboni (NVOC), and the like. One skilled in the art can identify other suitable amine protecting groups.

  Exemplary hydroxy protecting groups include those in which the hydroxy group is acylated or alkylated, such as benzyl, and trityl ethers and alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers, and allyl ethers.

  In addition, salts of the compounds described herein can exist in either hydrated or unhydrated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrate, dihydrate, and the like. Non-limiting examples of solvates include ethanol solvates, acetone solvates, and the like.

The term “solvate” means a solvent addition form comprising a stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. When the solvent is water, the solvate formed is a hydrate, and when the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by combining one or more water molecules with one of the substances, in which case water retains its molecular state as H ₂ O, and such combination results in one or more hydrates. Can be formed.

  The compounds, salts and prodrugs described herein can exist in several tautomeric forms, such as enol and imine forms, and keto and enamine forms and geometric isomers and mixtures thereof. Tautomers exist as a mixture of tautomeric sets in solution. In the solid form, usually one tautomer is dominant. Although described for one tautomer, this application includes all tautomers of the present compounds. A tautomer is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. This reaction causes a formal transfer of hydrogen atoms, which is not accompanied by switching of adjacent conjugated double bonds. In solutions where tautomerism is possible, a chemical equilibrium of the tautomers is reached. The exact ratio of tautomers depends on several factors including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerization is called tautomerism.

  Of the various types of tautomerism that are possible, two are commonly observed. Keto-enol tautomerism involves simultaneous shifts of electrons and hydrogen atoms.

  Tautomerization can be catalyzed by: base: 1. 1. deprotonation; 2. formation of delocalized anions (eg enolate); Protonation at different positions of the anion; acid: 1. 1. protonation; 2. formation of delocalized cations; Deprotonation at different positions adjacent to the cation.

  The term “analog” refers to a chemical compound that is structurally similar to the other but slightly different in composition (replacement of one atom by an atom of a different element or in the presence of a particular functional group, Or as a replacement of one functional group with another functional group). Thus, an analog is a compound that is similar or equivalent in function and appearance to a reference compound, but not in structure or origin.

  A “patient”, “subject” or “host” to be treated by the subject method can mean a human or non-human animal, such as a mammal, fish, bird, reptile, or amphibian. Thus, the subject of the methods disclosed herein can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not indicate a particular age or gender. Thus, adult and neonatal subjects, and fetuses are intended to be included regardless of whether male or female. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease or disorder.

  The term “prophylactic” or “therapeutic” treatment is art-recognized and includes administration of one or more subject compositions to a host. If administered prior to clinical symptoms of an undesired condition (eg, host animal disease or other undesired condition), then the treatment is prophylactic, i.e., this causes the host to develop an undesired condition. Protection, while administered after the sign of an undesired condition, the treatment is therapeutic (i.e. intended to reduce, ameliorate, or stabilize an existing undesired condition or its side effects. )

  The terms “therapeutic agent”, “drug”, “drug” and “bioactive substance” are art-recognized and act locally or systemically in a patient or subject to treat a disease or condition. Includes molecules and other agents that are biologically, physiologically or pharmacologically active substances to be treated. The term includes, but is not limited to, pharmaceutically acceptable salts and prodrugs thereof. Such agents can be acidic, basic, or salt; they can be neutral molecules, polar molecules, or molecular complexes that are capable of hydrogen bonding; It may be a prodrug in the form of an ether, ester, amide, etc. that is biologically activated when administered to a subject.

  The phrase “therapeutically effective amount” or “pharmaceutically effective amount” is an art-recognized term. In certain embodiments, the term indicates the amount of therapeutic agent that produces some desired effect at a reasonable benefit / risk ratio applicable to any medical treatment. In certain embodiments, the term indicates the amount necessary or sufficient to eliminate, reduce, or maintain the target of a particular therapeutic regimen. Effective amounts may vary depending on factors such as the disease or condition being treated, the particular target construct being administered, the size of the subject or the severity of the disease or condition. One skilled in the art can empirically determine the effective amount of a particular compound without necessitating undue experimentation. In certain embodiments, the therapeutically effective amount of a therapeutic agent for in vivo use will likely depend on a number of factors including the following: the rate of release of the agent from the polymer matrix (which in part is Depending on the chemical and physical properties of the polymer); the identity of the agent; the mode and method of administration; and any other material that is incorporated into the polymer matrix in addition to the agent.

  The term “ED50” is approved in the art. In certain embodiments, an ED50 means the dose of a drug that produces 50% of its maximal response or effect, or a dose that produces a predetermined response in 50% of a test subject or preparation. The term “LD50” is approved in the art. In certain embodiments, LD50 refers to the dose of a drug that is lethal in 50% of test subjects. The term “therapeutic index” is an art-recognized term that indicates the therapeutic index of a drug defined as LD50 / ED50.

The term “IC ₅₀ ” or “50% inhibitory concentration” is required for 50% inhibition of a biological process or component of a process, eg, a protein, subunit, organelle, ribonucleoprotein, etc. Intended to indicate the concentration of a substance (eg, compound or drug).

  For any chemical compound, this application is intended to include all isotopes of atoms occurring in the compound. Isotopes include those atoms having the same atomic number but different mass numbers. As a general example, without limitation, isotopes of hydrogen include tritium and deuterium, and carbon isotopes include C-13 and C-14.

  Where a bond to a substituent is shown across a bond that connects two atoms in the ring, then such a substituent can be bonded to any atom in the ring. If a substituent is listed without indicating through which atom it is attached to the rest of the compound of the given formula, then such substituent is such a substituent. It can be bonded through any atom in it. Combinations of substituents and / or variables are allowed, but only if such combinations yield stable compounds.

When an atomic or chemical moiety is followed by a subscripted numerical range (eg, C _1-6 ), it is meant to include each numerical value within that range as well as all intermediate ranges. For example, “C _1-6 alkyl” is 1, 2, 3, 4, 5, 6, _{1-6, 1-5,} 1-4, 1-3, 1-2, 2-6, 2-5. It is meant to include alkyl groups having 2-4, 2-3, 3-6, 3-5, 3-4, 4-6, 4-5, and 5-6 carbons.

The term “alkyl” is both branched (eg, isopropyl, tert-butyl, isobutyl), linear, eg, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl), and It is intended to include cycloalkyl (eg, alicyclic) groups (eg, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups . Such aliphatic hydrocarbon groups have the specified number of carbon atoms. For example, C _1-6 alkyl is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , and C ₆ alkyl groups. As used herein, “lower alkyl” refers to an alkyl group having 1 to 6 carbon atoms in the skeleton of the carbon chain. “Alkyl” further includes alkyl groups having oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more hydrocarbon backbone carbon atoms. In certain embodiments, a straight chain or branched chain alkyl is 6 or less (eg, C ₁ -C ₆ for straight chain, C ₃ -C ₆ for branched chain), eg, 4 or less carbons in its backbone. Has atoms. Similarly, certain cycloalkyls have from 3 to 8 carbon atoms in their ring structure, for example 5 or 6 carbons in the ring structure.

  The term “substituted alkyl” refers to an alkyl moiety having a substituent that replaces hydrogen on one or more carbons of the hydrocarbon backbone. Examples of such substituents include: alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl , Alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), Acylamino (alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido Amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic Tribe part. Cycloalkyls can be further substituted, for example, with the substituents described above. An “alkylaryl” or “aralkyl” moiety is an alkyl substituted with an aryl (eg, phenylmethyl (benzyl)). Unless otherwise stated, the terms “alkyl” and “lower alkyl” include linear, branched, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkyl or lower alkyl, respectively.

  The term “alkenyl” refers to a linear, branched or cyclic hydrocarbon group of 2 to about 24 carbon atoms containing at least one double bond, such as ethenyl, n-propenyl, isopropenyl, n-butenyl, And isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, tetracocenyl, cyclopentenyl, cyclohexenyl, cyclooctenyl, and the like. Generally, but not necessarily again, an alkenyl group can contain 2 to about 18 carbon atoms, more particularly 2 to 12 carbon atoms. The term “lower alkenyl” refers to an alkenyl group of 2 to 6 carbon atoms, and the specific term “cycloalkenyl” intends a cyclic alkenyl group, preferably having 5 to 8 carbon atoms. The term “substituted alkenyl” refers to an alkenyl substituted with one or more substituents, and the terms “heteroatom-containing alkenyl” and “heteroalkenyl” have at least one carbon atom replaced with a heteroatom. Alkenyl or heterocycloalkenyl (eg heterocyclohexenyl) is indicated. Unless otherwise stated, the terms “alkenyl” and “lower alkenyl” include linear, branched, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkenyl and lower alkenyl, respectively.

  The term “alkynyl” refers to a straight or branched hydrocarbon group of 2 to 24 carbon atoms containing at least one triple bond, such as ethynyl, n-propynyl, and the like. In general, but not necessarily again, an alkynyl group can contain from 2 to about 18 carbon atoms, and more specifically can contain from 2 to 12 carbon atoms. The term “lower alkynyl” intends an alkynyl group of 2 to 6 carbon atoms. The term “substituted alkynyl” refers to alkynyl substituted with one or more substituents, and the terms “heteroatom-containing alkynyl” and “heteroalkynyl” have at least one carbon atom replaced with a heteroatom. Indicates alkynyl. Unless otherwise stated, the terms “alkynyl” and “lower alkynyl” include linear, branched, unsubstituted, substituted, and / or heteroatom-containing alkynyl and lower alkynyl, respectively.

The terms “alkyl”, “alkenyl”, and “alkynyl” are intended to include moieties that are diradicals, ie, have two points of attachment. A non-limiting example of such an alkyl moiety that is a diradical is —CH ₂ CH ₂ ——a C ₂ alkyl group attached to the remainder of the molecule through each terminal carbon atom via a covalent bond.

The term “alkoxy” refers to an alkyl group attached through a single terminal ether linkage; that is, an “alkoxy” group can be represented as —O-alkyl, where alkyl is as defined above. As defined in A “lower alkoxy” group intends an alkoxy group containing 1 to 6 carbon atoms and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, t-butyloxy, and the like. Preferred substituents identified herein as “C ₁ -C ₆ alkoxy” or “lower alkoxy” contain 1 to 3 carbon atoms, and particularly preferred such substituents are 1 or 2 carbon atoms. (Ie, methoxy and ethoxy).

  The term “aryl” refers to a single aromatic ring or multiple aromatic rings fused together, directly linked, or indirectly linked so that different aromatic rings are attached to a common group such as a methylene or ethylene moiety. An aromatic substituent containing Aryl groups can contain 5 to 20 carbon atoms, and particularly preferred aryl groups can contain 5 to 14 carbon atoms. Examples of aryl groups include: benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like . In addition, the term “aryl” refers to polycyclic aryl groups such as tricyclic, bicyclic, such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, methylenedioxyphenyl Quinoline, isoquinoline, naphthridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine. Those aryl groups having heteroatoms in the ring structure may also be referred to as “aryl heterocycles”, “heterocycles”, “heteroaryls” or “heteroaromatics”. The aromatic ring may be substituted at one or more ring positions by such substituents as described above, eg, as follows: halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, Aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphinate, Cyano, amino (alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino ), Acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoro Methyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings (not aromatic) to form polycyclic systems (eg, tetralin, methylenedioxyphenyl). Unless otherwise stated, the term “aryl” includes unsubstituted, substituted, and / or heteroatom-containing aromatic substituents.

  The term “alkaryl” refers to an aryl group having an alkyl substituent, and the term “aralkyl” refers to an alkyl group having an aryl substituent, where “aryl” and “alkyl” are defined above. That's right. Exemplary aralkyl groups contain 6 to 24 carbon atoms, and particularly preferred aralkyl groups contain 6 to 16 carbon atoms. Examples of aralkyl groups include, but are not limited to: benzyl, 2-phenyl-ethyl, 3-phenyl-propyl, 4-phenyl-butyl, 5-phenyl-pentyl, 4-phenylcyclohexyl, 4 -Benzylcyclohexyl, 4-phenylcyclohexylmethyl, 4-benzylcyclohexylmethyl, and the like. Examples of the alkaryl group include p-methylphenyl, 2,4-dimethylphenyl, p-cyclohexylphenyl, 2,7-dimethylnaphthyl, 7-cyclooctylnaphthyl, 3-ethyl-cyclopenta-1,4-diene, and the like. Is mentioned.

  The term “heterocyclyl” or “heterocyclic group” includes closed ring structures containing one or more heteroatoms, such as 3- to 10-, or 4- to 7-membered rings. “Heteroatom” includes atoms of any element other than carbon or hydrogen. Examples of heteroatoms include nitrogen, oxygen, sulfur and phosphorus.

Heterocyclyl groups can be saturated or unsaturated and include pyrrolidine, oxolane, thiolane, piperidine, piperazine, morpholine, lactone, lactams such as azetidinone and pyrrolidinone, sultam, and sultone. Heterocyclic groups such as pyrrole and furan can have aromatic character. They include fused ring structures such as quinoline and isoquinoline. Other examples of heterocyclic groups include pyridine and purine. Heterocycles can be substituted at one or more positions with substituents as described above, eg, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxy Rate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (alkylcarbonyl) Amino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, O carboxylate, sulfate, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, or an aromatic or heteroaromatic moiety. A heterocyclic group also has one or more member atoms such as lower alkyl, lower alkenyl, lower alkoxy, lower alkylthio, lower alkylamino, lower alkylcarboxyl, nitro, hydroxyl, --CF ₃ , or --CN, And so on.

  The term “halo” or “halogen” refers to fluoro, chloro, bromo, and iodo. “Counterion” is used to represent small, negatively charged species such as fluoride, chloride, bromide, iodide, hydroxide, acetate, and sulfate. The term sulfoxide refers to sulfur attached to two different carbon atoms and one oxygen, and the S—O bond is a diagram, a double bond (S═O), an uncharged single bond (S—O) or It can be expressed using a single bond [S (+)-O (-)] with a charge.

The term “substituted” in “substituted alkyl”, “substituted aryl” and the like, as implied in some of the above definitions, is a carbon (or other) atom in an alkyl, aryl, or other moiety. Means that at least one hydrogen atom bonded to is replaced by one or more non-hydrogen substituents. Examples of such substituents include, but are not limited to: functional groups such as halo, hydroxyl, silyl, sulfhydryl, C ₁ -C ₂₄ alkoxy, C ₂ -C ₂₄ alkenyloxy, C ₂ -C _{24 alkynyloxy,} C 5 _{-C 20} aryloxy, acyl _(e.g., C 2 _{-C 24} alkylcarbonyl (-CO- alkyl) and _C 6 _{-C 20} arylcarbonyl (-CO- aryl)), acyloxy (- O- _acyl), C 2 _{-C 24} alkoxycarbonyl (- (CO) -O- _alkyl), C 6 _{-C 20} aryloxycarbonyl (- (CO) -O- _aryl), C 2 _{-C 24} alkylcarbonyl isocyanatomethyl (-O- (CO) -O- _alkyl), C 6 _{-C 20} aryl carbonium diisocyanatohexane (-O- (CO) -O- ants Le), carboxy (-COOH), carboxylato (-COO-), carbamoyl (- (CO) - _NH 2), mono _- (C 1 _{-C 24} alkyl) - substituted carbamoyl (- (CO) -NH ( C ₁ -C ₂₄ alkyl)), di - _(C 1 -C ₄ alkyl) - substituted carbamoyl _{(- (CO) - N (} C 1 -C 24 _alkyl) 2), mono - substituted arylcarbamoyl (- (CO ) -NH-aryl), thiocarbamoyl (— (CS) —NH ₂ ), carbamide (—NH— (CO) —NH ₂ ), cyano (—CN), isocyano (—N ⁺ C ⁻ ), cyanato (— O - CN), isocyanato ^(-ON + C ^-), isothiocyanato (-S-CN), azido ^{(-N = N + = N -} ), formyl (- (CO) - H), thioformyl (- (CS) -H), amino (--NH _2), mono- - and di _- (C 1 _{-C 24} alkyl) - substituted amino, mono- - and di _- (C 5 _{-C 20} aryl) - substituted _amino, C 2 -C ₂₄ alkylamide (—NH— (CO) -alkyl), C ₆ -C ₂₀ arylamide (—NH— (CO) -aryl), imino (—CR═NH, where R = hydrogen, C ₁ —C _{24 alkyl,} C 5 _{-C 20 aryl,} C 6 _{-C 24 alkaryl,} C 6 _{-C 24} aralkyl, and the like), alkylimino (-CR = N (alkyl), wherein, R = hydrogen, alkyl, aryl , Alkaryl, etc.), arylimino (—CR═N (aryl), where R = hydrogen, alkyl, aryl, alkaryl, etc.), nitro (—NO ₂ ), nitroso (—NO), Sulfo (—SO ₂ —OH), sulfonate (—SO ₂ —O ⁻ ), C ₁ -C ₂₄ alkylsulfanyl (—S-alkyl; also referred to as “alkylthio”), arylsulfanyl (—S-aryl; “arylthio”) referred _to), C 1 _{-C 24} alkylsulfinyl (- (SO) - _alkyl), C 5 _{-C 20} arylsulfinyl (- (SO) - _aryl), C 1 _{-C 24} alkylsulfonyl (-SO ₂ - alkyl) , _C 5 _{-C 20} arylsulfonyl (-SO ₂ - aryl), phosphono _{(-P (O) (OH)} 2), phosphonato ^{(-P (O) (O -} ) 2), phosphinato (-P (O) ^(O -)), phospho _(-PO 2), and phosphino _(-PH 2); and hydrocarbyl moiety _C 1 _{-C 24} alkyl, _{C 2} - _{24 alkenyl,} C 2 _{-C 24 alkynyl,} C 5 _{-C 20 aryl,} C 6 _{-C 24} alkaryl, and _C 6 _{-C 24} aralkyl.

  In addition, the functional group may be further substituted with one or more additional functional groups, or one or more hydrocarbyl moieties, such as those specifically listed above, if the particular group allows. Similarly, the hydrocarbyl moiety can be further substituted with one or more functional groups or additional hydrocarbyl moieties, such as those specifically listed.

  When the term “substituted” appears before the list of possible substituted groups, the term is intended to apply to all members of the group. For example, the phrase “substituted alkyl, alkenyl, and aryl” should be interpreted as “substituted alkyl, substituted alkenyl, and substituted aryl.” Similarly, if the term “heteroatom-containing” appears before the list of possible heteroatom-containing groups, the term is intended to apply to all members of the group. For example, the phrase “heteroatom-containing alkyl, alkenyl, and aryl” should be interpreted as “heteroatom-containing alkyl, substituted alkenyl, and substituted aryl.”

  “Optional” or “optional” may or may not occur in the situation described next, so that the description shall indicate when the situation occurs and when the situation does not occur. It means to include. For example, the phrase “optionally substituted” means that a non-hydrogen substituent may or may not be present on a given atom, so that the description indicates that a non-hydrogen substituent is present. Includes structures and structures where no non-hydrogen substituents are present.

  The terms "stable compound" and "stable structure" indicate a compound that is robust enough to survive isolation, optionally purification from a reaction mixture, and formulation into an effective therapeutic agent. Is meant.

  The term “free compound” is used herein to describe a compound in an unbound state.

  Throughout the description, where a composition is described as having, containing, or containing a particular component, the composition also consists essentially of, or consists of, the listed components. Is contemplated. Similarly, where a method or process is described as having, containing, or comprising a particular process step, the process also consists essentially of or consists of the listed process steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the compositions and methods described herein are operable. Moreover, two or more steps or operations can be performed simultaneously.

  The term “small molecule” is an approved term in the art. In certain embodiments, the term refers to a molecule having a molecular weight of less than about 2000 amu, or less than about 1000 amu, and even less than about 500 amu.

  All percentages and ratios used herein are by weight unless otherwise specified.

  The term “neoplasm” refers to any abnormal mass of cells or tissues as a result of abnormal growth. Neoplasms can be benign, potentially malignant (precancerous), or malignant (cancerous). An adenoma is an example of a neoplasm.

  The terms “adenoma”, “colon adenoma” and “polyp” are used herein to describe any precancerous neoplasm of the colon.

  The term “colon” is intended herein to include the right colon (including the cecum), the transverse colon, the left colon, and the rectum.

  The terms “colorectal cancer” and “colon cancer” are used interchangeably herein and refer to any cancerous neoplasm of the colon (including the rectum as defined above).

  The term “gene expression” or “protein expression” refers to any information about the amount of gene transcript or protein present in a sample, as well as information about the rate at which the gene or protein is produced, accumulates or degrades. (Eg, reporter gene data, data from nuclear run-off experiments, pulse chase data, etc.). Certain types of data can be considered related to both gene and protein expression. For example, the protein level in a cell reflects the level of protein as well as the level of transcription, and such data is intended to be included by the phrase “gene or protein expression information”. Such information may be given in the form of quantities / cells, quantities relative to a control gene or protein, unitless measurements, etc .; the term “information” is not limited to any particular meaning of the expression, but relevant information Is intended to mean any expression that provides The term “expression level” refers to the amount reflected in or derivable from gene or protein expression data, regardless of whether the data is directed to gene transcript accumulation or protein accumulation or protein synthesis rate, etc. .

  The terms “healthy” and “normal” are used interchangeably herein to indicate a subject or a particular cell or tissue that lacks a disease state (at least to the limit of detection).

  The term “nucleic acid” refers to polynucleotides such as deoxyribonucleic acid (DNA) and, where appropriate, ribonucleic acid (RNA). The term also includes analogs of either RNA or DNA composed of nucleotide analogs, and single strands (eg, sense or antisense) and doubles, as applicable to the described embodiments. It should be understood to include strand polynucleotides. In some embodiments, “nucleic acid” refers to an inhibiting nucleic acid. Some categories of inhibitory nucleic acid compounds include antisense nucleic acids, RNAi constructs, and catalytic nucleic acid constructs. Such categories of nucleic acids are well known in the art.

  Embodiments described herein modulate SCD activity (eg, 15-PGDH activity), modulate tissue prostaglandin levels, and / or modulate 15-PGDH activity and / or prostaglandin levels. It relates to compounds and methods for treating diseases, disorders, or conditions for which it is desired.

  “Inhibitors”, “activators” and “modulators” of 15-PGDH expression or 15-PGDH activity are identified using in vitro and in vivo assays for 15-PGDH expression or 15-PGDH activity, respectively, Used to indicate activation or regulatory molecules such as ligands, agonists, antagonists, and their homologues and mimetics. The term “modulator” includes inhibitors and activators. Inhibitors, for example, inhibit or bind to the expression of 15-PGDH, partially or totally blocking stimulation, reducing, preventing, delaying activation and deactivating 15-PGDH activity. An agent that activates, desensitizes, or down-regulates, eg, an antagonist. An activator, for example, induces or activates or binds to the expression of 15-PGDH to stimulate, stabilize, increase, release, activate, promote or enhance activation of 15-PGDH. Agents that are sensitized or up-regulated, eg, agonists. Modulators include natural and synthetic ligands, small chemical molecules, and the like.

  The 15-PGDH inhibitors described herein can provide a pharmacological method for increasing prostaglandin levels in tissues. Known activities of prostaglandins include promoting hair growth, promoting skin pigmentation, and promoting the appearance of skin darkening or skin tanning. Known activities of prostaglandins include ameliorating pulmonary arterial hypertension. The 15-PGDH inhibitors described herein also increase resistance to radiation-induced tissue damage, increase resistance to environmental exposure to radiation, increase the fitness of bone marrow or other types of transplants Increase the number of stem cells to increase (by in vivo exposure to the 15-PGDH inhibitors described herein for increasing stem cell number prior to collection of transplanted tissue, or collection prior to transplantation into a recipient host Can be used to increase the number of tissue stem cells for purposes including (by ex vivo exposure of the treated tissue or by treatment of the transplant patient). The 15-PGDH inhibitors described herein also promote liver regeneration, including liver regeneration after hepatectomy and liver regeneration following toxic insults (which can be, for example, toxic insults of acetaminophen overdose) Can be used for purposes including Prostaglandin signaling is also known to promote wound healing, protect the stomach from ulceration, and promote healing of gastric and intestinal ulcers. In addition, the 15-PGDH inhibitors described herein can enhance the activity of human keratinocytes in the “healing” of scratches across cultures of keratinocytes. Thus, the 15-PGDH inhibitors described herein can also be used to heal other tissues such as, but not limited to, skin ulcers and, for example, but not limited to diabetic ulcers . Further, the 15-PGDH inhibitors described herein can be used for the treatment of erectile dysfunction.

  The 15-PGDH inhibitors described herein are identified using assays in which the putative modulator compound is applied to cells that express 15-PGDH and then a functional effect on 15-PGDH activity is determined. be able to. A sample or assay containing 15-PGDH treated with a potential activator, inhibitor, or modulator is compared to a control sample that does not have an inhibitor, activator, or modulator, and the extent of effect is tested Is done. Control samples (no treatment with modulator) are assigned a relative 15-PGDH activity value of 100%. Inhibition of 15-PGDH is achieved when the 15-PGDH activity value relative to the control is about 80%, optionally 50% or 25%, 10%, 5% or 1%.

  The agent to be tested as a modulator of SCD (eg, 15-PGDH) can be any small chemical molecule or compound. Typically, the test compound is a small chemical molecule, natural product, or peptide. The assay is designed to screen large compound libraries by automating the assay process and providing compounds from any source that favors the assay, which are typically performed simultaneously (e.g., In microtiter format on microtiter plates in robotic assays). Modulators also include agents designed to increase the level of 15-PGDH mRNA or the level of translation from mRNA.

式中、ｎ＝０−２であり；
Ｘ^６はＮまたはＣＲ^ｃであり；
Ｒ^１は、−（ＣＨ_２）ｎ_１ＣＨ_３（ｎ_１＝０−７）、

式中、ｎ_２＝０−６であり、Ｘは下記のいずれかである：
ＣＦ_ｙＨ_ｚ（ｙ＋ｚ＝３）、ＣＣｌ_ｙＨ_ｚ（ｙ＋ｚ＝３）、ＯＨ、ＯＡｃ、ＯＭｅ、Ｒ^７１、ＯＲ^７２、ＣＮ、Ｎ（Ｒ^７３）_２、

を含む分枝または直鎖アルキルからなる群より選択され；
Ｒ^５は、Ｈ、ＯＨ、Ｃｌ、Ｆ、ＮＨ_２、Ｎ（Ｒ^７６）_２、およびＯＲ^７７からなる群より選択され_；
Ｒ^６およびＲ^７はそれぞれ独立して、下記の１つとすることができ：

各Ｒ^８ _、Ｒ^９ _、Ｒ^１０ _、Ｒ^１１ _、Ｒ^１２ _、Ｒ^１３ _、Ｒ^１４ _、Ｒ^１５ _、Ｒ^１６ _、Ｒ^１７ _、Ｒ^１８ _、Ｒ^１９ _、Ｒ^２０ _、Ｒ^２１ _、Ｒ^２２ _、Ｒ^２３ _、Ｒ^２４ _、Ｒ^２５ _、Ｒ^２６ _、Ｒ^２７ａ _、Ｒ^２７ｂ _、Ｒ^２８ _、Ｒ^２９ _、Ｒ^３０ _、Ｒ^３１ _、Ｒ^３２ _、Ｒ^３３ _、Ｒ^３４ _、Ｒ^３５ _、Ｒ^３６ _、Ｒ^３７ _、Ｒ^３８ _、Ｒ^３９ _、Ｒ^４０ _、Ｒ^４１ _、Ｒ^４２ _、Ｒ^４３ _、Ｒ^４４ _、Ｒ^４５ _、Ｒ^４６ _、Ｒ^４７ _、Ｒ^４８ _、Ｒ^４９ _、Ｒ^５０ _、Ｒ^５１ _、Ｒ^５２ _、Ｒ^５３ _、Ｒ^５４ _、Ｒ^５５ _、Ｒ^５６ _、Ｒ^５７ _、Ｒ^５８ _、Ｒ^５９ _、Ｒ^６０ _、Ｒ^６１ _、Ｒ^６２ _、Ｒ^６３ _、Ｒ^６４ _、Ｒ^６５ _、Ｒ^６６ _、Ｒ^６７ _、Ｒ^６８ _、Ｒ^６９ _、Ｒ^７０ _、Ｒ^７１ _、Ｒ^７２ _、Ｒ^７３ _、Ｒ^７４ _、Ｒ^７６、Ｒ^７７、およびＲ^ｃは同じかまたは異なり、かつ、水素、置換もしくは非置換Ｃ_１−Ｃ_２４アルキル、Ｃ_２−Ｃ_２４アルケニル、Ｃ_２−Ｃ_２４アルキニル、Ｃ_３−Ｃ_２０アリール、５−６個の環原子を含むヘテロシクロアルケニル（ここで、１−３個の環原子は、Ｎ、ＮＨ、Ｎ（Ｃ_１−Ｃ_６アルキル）、ＮＣ（Ｏ）（Ｃ_１−Ｃ_６アルキル）、Ｏ、およびＳから独立して選択される）、５−１４個の環原子を含むヘテロアリールまたはヘテロシクリル（ここで、１−６個の環原子は、Ｎ、ＮＨ、Ｎ（Ｃ_１−Ｃ_３アルキル）、Ｏ、およびＳから独立して選択される）、Ｃ_６−Ｃ_２４アルカリル、Ｃ_６−Ｃ_２４アラルキル、ハロ、シリル、ヒドロキシル、スルフヒドリル、Ｃ_１−Ｃ_２４アルコキシ、Ｃ_２−Ｃ_２４アルケニルオキシ、Ｃ_２−Ｃ_２４アルキニルオキシ、Ｃ_５−Ｃ_２０アリールオキシ、アシル（例えば、Ｃ_２−Ｃ_２４アルキルカルボニル（−−ＣＯ−アルキル）およびＣ_６−Ｃ_２０アリールカルボニル（−ＣＯ−アリール））、アシルオキシ（−Ｏ−アシル）、Ｃ_２−Ｃ_２４アルコキシカルボニル（−（ＣＯ）−Ｏ−アルキル）、Ｃ_６−Ｃ_２０アリールオキシカルボニル（−（ＣＯ）−Ｏ−アリール）、Ｃ_２−Ｃ_２４アルキルカルボナト（−Ｏ−（ＣＯ）−Ｏ−アルキル）、Ｃ_６−Ｃ_２０アリールカルボナト（−Ｏ−（ＣＯ）−Ｏ−アリール）、カルボキシ（−ＣＯＯＨ）、カルボキシラト（−ＣＯＯ⁻）、カルバモイル（−（ＣＯ）−−ＮＨ_２）、Ｃ_１−Ｃ_２４アルキル−カルバモイル（−（ＣＯ）−ＮＨ（Ｃ_１−Ｃ_２４アルキル））、アリールカルバモイル（−（ＣＯ）−ＮＨ−アリール）、チオカルバモイル（−（ＣＳ）−ＮＨ_２）、カルバミド（−ＮＨ−（ＣＯ）−ＮＨ_２）、シアノ（−ＣＮ）、イソシアノ（−Ｎ^＋Ｃ⁻）、シアナト（−Ｏ−ＣＮ）、イソシアナト（−Ｏ−Ｎ^＋＝Ｃ⁻）、イソチオシアナト（−Ｓ−ＣＮ）、アジド（−Ｎ＝Ｎ^＋＝Ｎ⁻）、ホルミル（−−（ＣＯ）−−Ｈ）、チオホルミル（−−（ＣＳ）−−Ｈ）、アミノ（−−ＮＨ_２）、Ｃ_１−Ｃ_２４アルキルアミノ、Ｃ_５−Ｃ_２０アリールアミノ、Ｃ_２−Ｃ_２４アルキルアミド（−ＮＨ−（ＣＯ）−アルキル）、Ｃ_６−Ｃ_２０アリールアミド（−ＮＨ−（ＣＯ）−アリール）、スルホンアミド（−ＳＯ_２Ｎ（Ｒ）_２、式中、Ｒは独立してＨ、アルキル、アリールまたはヘテロアリールである）、イミノ（−ＣＲ＝ＮＨ、式中、Ｒは水素、Ｃ_１−Ｃ_２４アルキル、Ｃ_５−Ｃ_２０アリール、Ｃ_６−Ｃ_２４アルカリル、Ｃ_６−Ｃ_２４アラルキル、などである）、アルキルイミノ（−ＣＲ＝Ｎ（アルキル）、式中、Ｒ＝水素、アルキル、アリール、アルカリル、アラルキル、などである）、アリールイミノ（−ＣＲ＝Ｎ（アリール）、式中、Ｒ＝水素、アルキル、アリール、アルカリル、などである）、ニトロ（−ＮＯ_２）、ニトロソ（−ＮＯ）、スルホ（−ＳＯ_２−ＯＨ）、スルホナト（−ＳＯ_２−Ｏ⁻）、Ｃ_１−Ｃ_２４アルキルスルファニル（−Ｓ−アルキル；「アルキルチオ」とも呼ばれる）、アリールスルファニル（−Ｓ−アリール；「アリールチオ」とも呼ばれる）、Ｃ_１−Ｃ_２４アルキルスルフィニル（−（ＳＯ）−アルキル）、Ｃ_５−Ｃ_２０アリールスルフィニル（−（ＳＯ）−アリール）、Ｃ_１−Ｃ_２４アルキルスルホニル（−ＳＯ_２−アルキル）、Ｃ_５−Ｃ_２０アリールスルホニル（−ＳＯ_２−アリール）、スルホンアミド（−ＳＯ_２−ＮＨ_２、−ＳＯ_２ＮＹ_２（式中、Ｙは独立してＨ、アリーリル（ａｒｌｙｌ）またはアルキルである）、ホスホノ（−Ｐ（Ｏ）（ＯＨ）_２）、ホスホナト（−Ｐ（Ｏ）（Ｏ⁻）_２）、ホスフィナト（−Ｐ（Ｏ）（Ｏ⁻））、ホスホ（−ＰＯ_２）、ホスフィノ（−−ＰＨ_２）、ポリアルキルエーテル（−［（ＣＨ_２）_ｎＯ］_ｍ）、ホスフェート、リン酸エステル［−ＯＰ（Ｏ）（ＯＲ）_２、式中、Ｒ＝Ｈ、メチルまたは他のアルキルである］、アミノ酸または生理的ｐＨで正または負電荷を有することが予想される他の部分を組み込んだ基、およびそれらの組み合わせからなる群より独立して選択され；
Ｒ^６がＨ、非置換チオフェン、または非置換チアゾールであり、およびＲ^１がブチルである場合、Ｒ^７は、水素ではなく；およびＲ^６がＨ、または非置換フェニル、チオフェン、またはチアゾールであり、およびＲ^１がベンジルまたは（ＣＨ_２）ｎ_５（ＣＨ_３）（ｎ_５＝０−５）である場合、Ｒ^７は非置換フェニルではない。 In some embodiments, the modulator of SCD can be an SCD inhibitor that can be administered to a tissue or blood of a subject in an amount effective to inhibit the activity of a short chain dehydrogenase enzyme. The SCD inhibitor can be a 15-PGDH inhibitor that can be administered to a tissue or blood of a subject in an amount effective to increase prostaglandin levels in the tissue or blood. The 15-PGDH inhibitor can include a compound having formula (I) as well as a pharmaceutically acceptable salt thereof:

Where n = 0-2;
X ⁶ is N or CR ^c ;
R ¹ is — (CH ₂ ) n ₁ CH ₃ (n ₁ = 0-7),

Where n ₂ = 0-6 and X is one of the following:
CF _y H _z (y + z = 3), CCl _y H _z (y + z = 3), OH, OAc, OMe, R ⁷¹ , OR ⁷² , CN, N (R ⁷³ ) ₂ ,

Selected from the group consisting of branched or straight chain alkyls including:
R ⁵ is selected from the group consisting of H, OH, Cl, F, NH ₂ , N (R ⁷⁶ ) ₂ , and OR ⁷⁷ _;
R ⁶ and R ⁷ can each independently be one of the following:

Each ^{_{R 8, R 9, R 10}} , R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19, R 20, R 21, R 22, R 23, R ^{_{24, R 25, R 26,}} R 27a, R 27b, R 28, R 29, R 30, R 31, R 32, R 33, R 34, R 35, R 36, R 37, R 38, R 39, ^{_{R 40, R 41, R 42}} , R 43, R 44, R 45, R 46, R 47, R 48, R 49, R 50, R 51, R 52, R 53, R 54, R 55, R 56 ^{_{, R 57, R 58, R}} 59, R 60, R 61, R 62, R 63, R 64, R 65, R 66, R 67, R 68, R 69, R 70, R 71, R 72, R ^{7 3} _, R ⁷⁴ _, R ⁷⁶ , R ⁷⁷ , and R ^c are the same or different and are hydrogen, substituted or unsubstituted C ₁ -C ₂₄ alkyl, C ₂ -C ₂₄ alkenyl, C ₂ -C ₂₄ alkynyl, C _3- C ₂₀ aryl, heterocycloalkenyl containing 5-6 ring atoms, wherein 1-3 ring atoms are N, NH, N (C ₁ -C ₆ alkyl), NC (O) ( C ₁ -C ₆ alkyl), independently selected from O, and S), heteroaryl or heterocyclyl containing 5-14 ring atoms, wherein 1-6 ring atoms are N, NH , N (C ₁ -C ₃ alkyl), independently selected from O and S), C ₆ -C ₂₄ alkaryl, C ₆ -C ₂₄ aralkyl, halo, silyl, hydroxyl, sulfhydryl, C ₁ -C ₂₄ alkoxy , _C 2 _{-C 24 alkenyloxy,} C 2 _{-C 24 alkynyloxy,} C 5 _{-C 20} aryloxy, acyl _(e.g., C 2 _{-C 24} alkylcarbonyl (--CO- alkyl) and _C 6 _{-C 20} aryl Carbonyl (—CO-aryl)), acyloxy (—O-acyl), C ₂ -C ₂₄ alkoxycarbonyl (— (CO) —O-alkyl), C ₆ -C ₂₀ aryloxycarbonyl (— (CO) —O) - _aryl), C 2 _{-C 24} alkylcarbonyl diisocyanatohexane (-O- (CO) -O- _alkyl), C 6 _{-C 20} aryl carbonium diisocyanatohexane (-O- (CO) -O- aryl), carboxy (-COOH ), Carboxylato (—COO ⁻ ), carbamoyl (— (CO) —NH ₂ ), C ₁ -C ₂₄ alkyl-carbamoyl (— (CO)) -NH _(C 1 _{-C 24} alkyl)), arylcarbamoyl (- (CO) -NH- aryl), thiocarbamoyl _{(- (CS) -NH 2)} , carbamide _{(-NH- (CO) -NH 2)} , cyano (-CN), isocyano ^(-N + C ^-), cyanato (-O-CN), isocyanato ^{(-O-N + = C -} ), isothiocyanato (-S-CN), azido (-N = ^{N +} = N ^-), formyl (- (CO) - H) , thioformyl (- (CS) - H) , amino _{(--NH 2), C 1 -C} 24 _alkylamino, C 5 _{-C 20 arylamino,} C 2 _{-C 24} alkylamido (-NH- (CO) - _alkyl), C 6 _{-C 20} aryl amide (-NH- (CO) - aryl), sulfonamide _{(-SO 2} N _(R) 2 Where R is independently H, alkyl, aryl or heteroaryl), imino (—CR═NH, wherein R is hydrogen, C ₁ -C ₂₄ alkyl, C ₅ -C ₂₀ aryl, C ₆ -C ₂₄ alkaryl, C _6. -C ₂₄ aralkyl, and the like), alkylimino (-CR = N (alkyl), wherein, R = hydrogen, alkyl, aryl, alkaryl, aralkyl, and the like), arylimino (-CR = N (aryl ), Wherein R = hydrogen, alkyl, aryl, alkaryl, etc.), nitro (—NO ₂ ), nitroso (—NO), sulfo (—SO ₂ —OH), sulfonate (—SO ₂ —O ^—) _), C 1 _{-C 24} alkylsulfanyl (-S- alkyl; also termed "alkylthio"), arylsulfanyl (-S- aryl; "arylthio" both _Barrel), C 1 _{-C 24} alkylsulfinyl (- (SO) - _alkyl), C 5 _{-C 20} arylsulfinyl (- (SO) - _aryl), C 1 _{-C 24} alkylsulfonyl (-SO ₂ - alkyl), C ₅ -C ₂₀ arylsulfonyl (—SO ₂ -aryl), sulfonamide (—SO ₂ —NH ₂ , —SO ₂ NY ₂ , wherein Y is independently H, aryl, or alkyl) , Phosphono (—P (O) (OH) ₂ ), phosphonate (—P (O) (O ⁻ ) ₂ ), phosphinate (—P (O) (O ⁻ )), phospho (—PO ₂ ), phosphino ( --PH _2), polyalkyl ethers _{(- [(CH 2) n} O] m), phosphate, phosphoric acid ester _{[-OP (O) (oR)} 2, where, R = H, methyl or other Alkyl], selected in an amino acid or physiological pH positive or incorporated group other portions that are expected to have a negative charge, and independently from the group consisting of;
When R ⁶ is H, unsubstituted thiophene, or unsubstituted thiazole, and R ¹ is butyl, R ⁷ is not hydrogen; and R ⁶ is H, or unsubstituted phenyl, thiophene, or thiazole And R ¹ is benzyl or (CH ₂ ) n ₅ (CH ₃ ) (n ₅ = 0-5), then R ⁷ is not unsubstituted phenyl.

In some embodiments, X ⁶ can be N or CH. R ⁶ can be a substituted or unsubstituted heterocyclyl containing 5-6 ring atoms. For example, R ⁶ can be substituted or unsubstituted thiophene, thiazole, oxazole, imidazole, pyridine, or phenyl. R ⁷ is H, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl, alkyl, or carboxy, such as carboxylic acid (—CO ₂ H), carboxy ester (—CO ₂ alkyl) and carboxamide [ -CON (H) may be selected from the group consisting of (alkyl) or _-CO 2 N _{(alkyl) 2].}

In other embodiments, when R ⁶ is substituted or unsubstituted thiophene, thiazole, oxazole, imidazole, pyridine, or phenyl, R ⁷ is not:

式中、ｎ＝０−２であり；
Ｘ^６はＮまたはＣＲ^ｃであり；
Ｘ^７はＮまたはＣであり；
Ｒ^１は、−（ＣＨ_２）ｎ_１ＣＨ_３（ｎ_１＝０−７）、

式中、ｎ_２＝０−６であり、Ｘは下記のいずれかである：
ＣＦ_ｙＨ_ｚ（ｙ＋ｚ＝３）、ＣＣｌ_ｙＨ_ｚ（ｙ＋ｚ＝３）、ＯＨ、ＯＡｃ、ＯＭｅ、Ｒ^７１、ＯＲ^７２、ＣＮ、Ｎ（Ｒ^７３）_２、

を含む分枝または直鎖アルキルからなる群より選択され；
Ｒ^５は、Ｈ、ＯＨ、Ｃｌ、Ｆ、ＮＨ_２、Ｎ（Ｒ^７６）_２、およびＯＲ^７７からなる群より選択され_；
Ｒ^７はそれぞれ独立して、下記の１つとすることができ：

各Ｒ^８ _、Ｒ^９ _、Ｒ^１０ _、Ｒ^１１ _、Ｒ^１２ _、Ｒ^１３ _、Ｒ^１４ _、Ｒ^１５ _、Ｒ^１６ _、Ｒ^１７ _、Ｒ^１８ _、Ｒ^１９ _、Ｒ^２０ _、Ｒ^２１ _、Ｒ^２２ _、Ｒ^２３ _、Ｒ^２４ _、Ｒ^２５ _、Ｒ^２６ _、Ｒ^２７ａ _、Ｒ^２７ｂ _、Ｒ^２８ _、Ｒ^２９ _、Ｒ^３０ _、Ｒ^３１ _、Ｒ^３２ _、Ｒ^３３ _、Ｒ^３４ _、Ｒ^３５ _、Ｒ^３６ _、Ｒ^３７ _、Ｒ^３８ _、Ｒ^３９ _、Ｒ^４０ _、Ｒ^４１ _、Ｒ^４２ _、Ｒ^４３ _、Ｒ^４４ _、Ｒ^４５ _、Ｒ^４６ _、Ｒ^４７ _、Ｒ^４８ _、Ｒ^４９ _、Ｒ^５０ _、Ｒ^５１ _、Ｒ^５２ _、Ｒ^５３ _、Ｒ^５４ _、Ｒ^５５ _、Ｒ^５６ _、Ｒ^５７ _、Ｒ^５８ _、Ｒ^５９ _、Ｒ^６０ _、Ｒ^６１ _、Ｒ^６２ _、Ｒ^６３ _、Ｒ^６４ _、Ｒ^６５ _、Ｒ^６６ _、Ｒ^６７ _、Ｒ^６８ _、Ｒ^６９ _、Ｒ^７０ _、Ｒ^７１ _、Ｒ^７２ _、Ｒ^７３ _、Ｒ^７４ _、Ｒ^７６、Ｒ^７７、Ｒ^ｃ、およびＲ^ｄは同じかまたは異なり、かつ、水素、置換もしくは非置換Ｃ_１−Ｃ_２４アルキル、Ｃ_２−Ｃ_２４アルケニル、Ｃ_２−Ｃ_２４アルキニル、Ｃ_３−Ｃ_２０アリール、５−６個の環原子を含むヘテロシクロアルケニル（ここで、１−３個の環原子は、Ｎ、ＮＨ、Ｎ（Ｃ_１−Ｃ_６アルキル）、ＮＣ（Ｏ）（Ｃ_１−Ｃ_６アルキル）、Ｏ、およびＳから独立して選択される）、５−１４個の環原子を含むヘテロアリールまたはヘテロシクリル（ここで、１−６個の環原子は、Ｎ、ＮＨ、Ｎ（Ｃ_１−Ｃ_３アルキル）、Ｏ、およびＳから独立して選択される）、Ｃ_６−Ｃ_２４アルカリル、Ｃ_６−Ｃ_２４アラルキル、ハロ、シリル、ヒドロキシル、スルフヒドリル、Ｃ_１−Ｃ_２４アルコキシ、Ｃ_２−Ｃ_２４アルケニルオキシ、Ｃ_２−Ｃ_２４アルキニルオキシ、Ｃ_５−Ｃ_２０アリールオキシ、アシル（例えば、Ｃ_２−Ｃ_２４アルキルカルボニル（−−ＣＯ−アルキル）およびＣ_６−Ｃ_２０アリールカルボニル（−ＣＯ−アリール））、アシルオキシ（−Ｏ−アシル）、Ｃ_２−Ｃ_２４アルコキシカルボニル（−（ＣＯ）−Ｏ−アルキル）、Ｃ_６−Ｃ_２０アリールオキシカルボニル（−（ＣＯ）−Ｏ−アリール）、Ｃ_２−Ｃ_２４アルキルカルボナト（−Ｏ−（ＣＯ）−Ｏ−アルキル）、Ｃ_６−Ｃ_２０アリールカルボナト（−Ｏ−（ＣＯ）−Ｏ−アリール）、カルボキシ（−ＣＯＯＨ）、カルボキシラト（−ＣＯＯ⁻）、カルバモイル（−（ＣＯ）−−ＮＨ_２）、Ｃ_１−Ｃ_２４アルキル−カルバモイル（−（ＣＯ）−ＮＨ（Ｃ_１−Ｃ_２４アルキル））、アリールカルバモイル（−（ＣＯ）−ＮＨ−アリール）、チオカルバモイル（−（ＣＳ）−ＮＨ_２）、カルバミド（−ＮＨ−（ＣＯ）−ＮＨ_２）、シアノ（−ＣＮ）、イソシアノ（−Ｎ^＋Ｃ⁻）、シアナト（−Ｏ−ＣＮ）、イソシアナト（−Ｏ−Ｎ^＋＝Ｃ⁻）、イソチオシアナト（−Ｓ−ＣＮ）、アジド（−Ｎ＝Ｎ^＋＝Ｎ⁻）、ホルミル（−−（ＣＯ）−−Ｈ）、チオホルミル（−−（ＣＳ）−−Ｈ）、アミノ（−−ＮＨ_２）、Ｃ_１−Ｃ_２４アルキルアミノ、Ｃ_５−Ｃ_２０アリールアミノ、Ｃ_２−Ｃ_２４アルキルアミド（−ＮＨ−（ＣＯ）−アルキル）、Ｃ_６−Ｃ_２０アリールアミド（−ＮＨ−（ＣＯ）−アリール）、スルホンアミド（−ＳＯ_２Ｎ（Ｒ）_２、式中、Ｒは独立してＨ、アルキル、アリールまたはヘテロアリールである）、イミノ（−ＣＲ＝ＮＨ、式中、Ｒは水素、Ｃ_１−Ｃ_２４アルキル、Ｃ_５−Ｃ_２０アリール、Ｃ_６−Ｃ_２４アルカリル、Ｃ_６−Ｃ_２４アラルキル、などである）、アルキルイミノ（−ＣＲ＝Ｎ（アルキル）、式中、Ｒ＝水素、アルキル、アリール、アルカリル、アラルキル、などである）、アリールイミノ（−ＣＲ＝Ｎ（アリール）、式中、Ｒ＝水素、アルキル、アリール、アルカリル、などである）、ニトロ（−ＮＯ_２）、ニトロソ（−ＮＯ）、スルホ（−ＳＯ_２−ＯＨ）、スルホナト（−ＳＯ_２−Ｏ⁻）、Ｃ_１−Ｃ_２４アルキルスルファニル（−Ｓ−アルキル；「アルキルチオ」とも呼ばれる）、アリールスルファニル（−Ｓ−アリール；「アリールチオ」とも呼ばれる）、Ｃ_１−Ｃ_２４アルキルスルフィニル（−（ＳＯ）−アルキル）、Ｃ_５−Ｃ_２０アリールスルフィニル（−（ＳＯ）−アリール）、Ｃ_１−Ｃ_２４アルキルスルホニル（−ＳＯ_２−アルキル）、Ｃ_５−Ｃ_２０アリールスルホニル（−ＳＯ_２−アリール）、スルホンアミド（−ＳＯ_２−ＮＨ_２、−ＳＯ_２ＮＹ_２（式中、Ｙは独立してＨ、アリーリル（ａｒｌｙｌ）またはアルキルである）、ホスホノ（−Ｐ（Ｏ）（ＯＨ）_２）、ホスホナト（−Ｐ（Ｏ）（Ｏ⁻）_２）、ホスフィナト（−Ｐ（Ｏ）（Ｏ⁻））、ホスホ（−ＰＯ_２）、ホスフィノ（−−ＰＨ_２）、ポリアルキルエーテル（−［（ＣＨ_２）_ｎＯ］_ｍ）、ホスフェート、リン酸エステル［−ＯＰ（Ｏ）（ＯＲ）_２、式中、Ｒ＝Ｈ、メチルまたは他のアルキルである］、アミノ酸または生理的ｐＨで正または負電荷を有することが予想される他の部分を組み込んだ基、およびそれらの組み合わせからなる群より独立して選択され；
Ｒ^１がブチルである場合、Ｒ^７は水素でなく；およびＲ^１が（ＣＨ_２）ｎ_５（ＣＨ_３）（ｎ_５＝０−５）である場合、Ｒ^７は非置換フェニルではない。 In still other embodiments, the 15-PGDH inhibitor can comprise a compound having formula (II) as well as a pharmaceutically acceptable salt thereof:

Where n = 0-2;
X ⁶ is N or CR ^c ;
X ⁷ is N or C;
R ¹ is — (CH ₂ ) n ₁ CH ₃ (n ₁ = 0-7),

Where n ₂ = 0-6 and X is one of the following:
CF _y H _z (y + z = 3), CCl _y H _z (y + z = 3), OH, OAc, OMe, R ⁷¹ , OR ⁷² , CN, N (R ⁷³ ) ₂ ,

Selected from the group consisting of branched or straight chain alkyls including:
R ⁵ is selected from the group consisting of H, OH, Cl, F, NH ₂ , N (R ⁷⁶ ) ₂ , and OR ⁷⁷ _;
Each R ⁷ can independently be one of the following:

Each ^{_{R 8, R 9, R 10}} , R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19, R 20, R 21, R 22, R 23, R ^{_{24, R 25, R 26,}} R 27a, R 27b, R 28, R 29, R 30, R 31, R 32, R 33, R 34, R 35, R 36, R 37, R 38, R 39, ^{_{R 40, R 41, R 42}} , R 43, R 44, R 45, R 46, R 47, R 48, R 49, R 50, R 51, R 52, R 53, R 54, R 55, R 56 ^{_{, R 57, R 58, R}} 59, R 60, R 61, R 62, R 63, R 64, R 65, R 66, R 67, R 68, R 69, R 70, R 71, R 72, R ^{7 3} _, R ⁷⁴ _, R ⁷⁶ , R ⁷⁷ , R ^c , and R ^d are the same or different and are hydrogen, substituted or unsubstituted C ₁ -C ₂₄ alkyl, C ₂ -C ₂₄ alkenyl, C ₂ -C _{24 alkynyl,} C 3 _{-C 20} aryl, heteroaryl cycloalkenyl containing 5-6 ring atoms (wherein 1-3 ring _{atoms, N, NH, N (C} 1 -C 6 alkyl), NC ( O) (C ₁ -C ₆ alkyl), independently selected from O and S), heteroaryl or heterocyclyl containing 5-14 ring atoms, wherein 1-6 ring atoms are N, NH, N (C ₁ -C ₃ alkyl), O, and S independently selected), C ₆ -C ₂₄ alkaryl, C ₆ -C ₂₄ aralkyl, halo, silyl, hydroxyl, sulfhydryl, C ₁ -C ₂₄ A _Kokishi, C 2 _{-C 24 alkenyloxy,} C 2 _{-C 24 alkynyloxy,} C 5 _{-C 20} aryloxy, acyl _(e.g., C 2 _{-C 24} alkylcarbonyl (--CO- alkyl) and _C 6 _{-C 20} arylcarbonyl (-CO- aryl)), acyloxy (-O- _acyl), C 2 _{-C 24} alkoxycarbonyl (- (CO) -O- _alkyl), C 6 _{-C 20} aryloxycarbonyl (- (CO) - O- _aryl), C 2 _{-C 24} alkylcarbonyl diisocyanatohexane (-O- (CO) -O- _alkyl), C 6 _{-C 20} aryl carbonium diisocyanatohexane (-O- (CO) -O- aryl), carboxy (- COOH), carboxylato (-COO ^-), carbamoyl _{(- (CO) - NH 2} ), C 1 -C 24 alkyl - carbamoyl (- CO) _-NH (C 1 _{-C 24} alkyl)), arylcarbamoyl (- (CO) -NH- aryl), thiocarbamoyl _{(- (CS) -NH 2)} , carbamide (-NH- (CO) -NH ₂ ), Cyano (—CN), isocyano (—N ⁺ C ⁻ ), cyanato (—O—CN), isocyanato (—O—N ⁺ = C ⁻ ), isothiocyanato (—S—CN), azide (—N═ N ⁺ = N ^-), formyl (- (CO) - H) , thioformyl (- (CS) - H) , amino _{(--NH 2), C 1 -C} 24 alkylamino, _{C 5} - C _{20 arylamino,} C 2 _{-C 24} alkylamido (-NH- (CO) - _alkyl), C 6 _{-C 20} aryl amide (-NH- (CO) - aryl), sulfonamide _(-SO 2 N (R ) _2, wherein, R Independently H, alkyl, aryl or heteroaryl), imino (-CR = NH, wherein, R represents _hydrogen, C 1 _{-C 24 alkyl,} C 5 _{-C 20 aryl,} C 6 _{-C 24} alkaryl, C ₆ -C ₂₄ aralkyl, etc.), alkylimino (—CR═N (alkyl), where R = hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (—CR═N (Aryl), where R = hydrogen, alkyl, aryl, alkaryl, etc.), nitro (—NO ₂ ), nitroso (—NO), sulfo (—SO ₂ —OH), sulfonate (—SO ₂ —) O ⁻ ), C ₁ -C ₂₄ alkylsulfanyl (—S-alkyl; also referred to as “alkylthio”), arylsulfanyl (—S-aryl; “arylthio” "Also _called), C 1 _{-C 24} alkylsulfinyl (- (SO) - _alkyl), C 5 _{-C 20} arylsulfinyl (- (SO) - _aryl), C 1 _{-C 24} alkylsulfonyl (-SO ₂ - alkyl ), C ₅ -C ₂₀ arylsulfonyl (—SO ₂ -aryl), sulfonamide (—SO ₂ —NH ₂ , —SO ₂ NY ₂ , wherein Y is independently H, aryl, or alkyl. ), Phosphono (—P (O) (OH) ₂ ), phosphonate (—P (O) (O ⁻ ) ₂ ), phosphinate (—P (O) (O ⁻ )), phospho (—PO ₂ ), phosphino (--PH _2), polyalkyl ethers _{(- [(CH 2) n} O] m), phosphate, phosphoric acid ester _{[-OP (O) (OR)} 2, where, R = H, methyl The other is other alkyl, selected amino acid or physiological pH positive or incorporated group other portions that are expected to have a negative charge, and independently from the group consisting of;
When R ¹ is butyl, R ⁷ is not hydrogen; and when R ¹ is (CH ₂ ) n ₅ (CH ₃ ) (n ₅ = 0-5), R ⁷ is not unsubstituted phenyl.

In some embodiments, R ⁷ is not:

式中、ｎ＝０−２であり；
Ｘ^６はＮまたはＣＲ^ｃであり；
Ｘ^７はＮまたはＣであり；
Ｒ^１は、−（ＣＨ_２）ｎ_１ＣＨ_３（ｎ_１＝０−７）、

式中、ｎ_２＝０−６であり、Ｘは下記のいずれかである：
ＣＦ_ｙＨ_ｚ（ｙ＋ｚ＝３）、ＣＣｌ_ｙＨ_ｚ（ｙ＋ｚ＝３）、ＯＨ、ＯＡｃ、ＯＭｅ、Ｒ^７１、ＯＲ^７２、ＣＮ、Ｎ（Ｒ^７３）_２、

（ｎ_４＝０−５）
を含む分枝または直鎖アルキルからなる群より選択され；
Ｒ^５は、Ｈ、ＯＨ、Ｃｌ、Ｆ、ＮＨ_２、Ｎ（Ｒ^７６）_２、およびＯＲ^７７からなる群より選択され_；
Ｒ^７はそれぞれ独立して、下記の１つとすることができ：

各Ｒ^８ _、Ｒ^９ _、Ｒ^１０ _、Ｒ^１１ _、Ｒ^１２ _、Ｒ^１３ _、Ｒ^１４ _、Ｒ^１５ _、Ｒ^１６ _、Ｒ^１７ _、Ｒ^１８ _、Ｒ^１９ _、Ｒ^２０ _、Ｒ^２１ _、Ｒ^２２ _、Ｒ^２３ _、Ｒ^２４ _、Ｒ^２５ _、Ｒ^２６ _、Ｒ^２７ａ _、Ｒ^２７ｂ _、Ｒ^２８ _、Ｒ^２９ _、Ｒ^３０ _、Ｒ^３１ _、Ｒ^３２ _、Ｒ^３３ _、Ｒ^３４ _、Ｒ^３５ _、Ｒ^３６ _、Ｒ^３７ _、Ｒ^３８ _、Ｒ^３９ _、Ｒ^４０ _、Ｒ^４１ _、Ｒ^４２ _、Ｒ^４３ _、Ｒ^４４ _、Ｒ^４５ _、Ｒ^４６ _、Ｒ^４７ _、Ｒ^７１ _、Ｒ^７２ _、Ｒ^７３ _、Ｒ^７４ _、Ｒ^７６、Ｒ^７７、Ｒ^ｃ、およびＲ^ｄは同じかまたは異なり、かつ、水素、置換もしくは非置換Ｃ_１−Ｃ_２４アルキル、Ｃ_２−Ｃ_２４アルケニル、Ｃ_２−Ｃ_２４アルキニル、Ｃ_３−Ｃ_２０アリール、５−６個の環原子を含むヘテロシクロアルケニル（ここで、１−３個の環原子は、Ｎ、ＮＨ、Ｎ（Ｃ_１−Ｃ_６アルキル）、ＮＣ（Ｏ）（Ｃ_１−Ｃ_６アルキル）、Ｏ、およびＳから独立して選択される）、５−１４個の環原子を含むヘテロアリールまたはヘテロシクリル（ここで、１−６個の環原子は、Ｎ、ＮＨ、Ｎ（Ｃ_１−Ｃ_３アルキル）、Ｏ、およびＳから独立して選択される）、Ｃ_６−Ｃ_２４アルカリル、Ｃ_６−Ｃ_２４アラルキル、ハロ、シリル、ヒドロキシル、スルフヒドリル、Ｃ_１−Ｃ_２４アルコキシ、Ｃ_２−Ｃ_２４アルケニルオキシ、Ｃ_２−Ｃ_２４アルキニルオキシ、Ｃ_５−Ｃ_２０アリールオキシ、アシル（例えば、Ｃ_２−Ｃ_２４アルキルカルボニル（−−ＣＯ−アルキル）およびＣ_６−Ｃ_２０アリールカルボニル（−ＣＯ−アリール））、アシルオキシ（−Ｏ−アシル）、Ｃ_２−Ｃ_２４アルコキシカルボニル（−（ＣＯ）−Ｏ−アルキル）、Ｃ_６−Ｃ_２０アリールオキシカルボニル（−（ＣＯ）−Ｏ−アリール）、Ｃ_２−Ｃ_２４アルキルカルボナト（−Ｏ−（ＣＯ）−Ｏ−アルキル）、Ｃ_６−Ｃ_２０アリールカルボナト（−Ｏ−（ＣＯ）−Ｏ−アリール）、カルボキシ（−ＣＯＯＨ）、カルボキシラト（−ＣＯＯ⁻）、カルバモイル（−（ＣＯ）−−ＮＨ_２）、Ｃ_１−Ｃ_２４アルキル−カルバモイル（−（ＣＯ）−ＮＨ（Ｃ_１−Ｃ_２４アルキル））、アリールカルバモイル（−（ＣＯ）−ＮＨ−アリール）、チオカルバモイル（−（ＣＳ）−ＮＨ_２）、カルバミド（−ＮＨ−（ＣＯ）−ＮＨ_２）、シアノ（−ＣＮ）、イソシアノ（−Ｎ^＋Ｃ⁻）、シアナト（−Ｏ−ＣＮ）、イソシアナト（−Ｏ−Ｎ^＋＝Ｃ⁻）、イソチオシアナト（−Ｓ−ＣＮ）、アジド（−Ｎ＝Ｎ^＋＝Ｎ⁻）、ホルミル（−−（ＣＯ）−−Ｈ）、チオホルミル（−−（ＣＳ）−−Ｈ）、アミノ（−−ＮＨ_２）、Ｃ_１−Ｃ_２４アルキルアミノ、Ｃ_５−Ｃ_２０アリールアミノ、Ｃ_２−Ｃ_２４アルキルアミド（−ＮＨ−（ＣＯ）−アルキル）、Ｃ_６−Ｃ_２０アリールアミド（−ＮＨ−（ＣＯ）−アリール）、スルホンアミド（−ＳＯ_２Ｎ（Ｒ）_２、式中、Ｒは独立してＨ、アルキル、アリールまたはヘテロアリールである）、イミノ（−ＣＲ＝ＮＨ、式中、Ｒは水素、Ｃ_１−Ｃ_２４アルキル、Ｃ_５−Ｃ_２０アリール、Ｃ_６−Ｃ_２４アルカリル、Ｃ_６−Ｃ_２４アラルキル、などである）、アルキルイミノ（−ＣＲ＝Ｎ（アルキル）、式中、Ｒ＝水素、アルキル、アリール、アルカリル、アラルキル、などである）、アリールイミノ（−ＣＲ＝Ｎ（アリール）、式中、Ｒ＝水素、アルキル、アリール、アルカリル、などである）、ニトロ（−ＮＯ_２）、ニトロソ（−ＮＯ）、スルホ（−ＳＯ_２−ＯＨ）、スルホナト（−ＳＯ_２−Ｏ⁻）、Ｃ_１−Ｃ_２４アルキルスルファニル（−Ｓ−アルキル；「アルキルチオ」とも呼ばれる）、アリールスルファニル（−Ｓ−アリール；「アリールチオ」とも呼ばれる）、Ｃ_１−Ｃ_２４アルキルスルフィニル（−（ＳＯ）−アルキル）、Ｃ_５−Ｃ_２０アリールスルフィニル（−（ＳＯ）−アリール）、Ｃ_１−Ｃ_２４アルキルスルホニル（−ＳＯ_２−アルキル）、Ｃ_５−Ｃ_２０アリールスルホニル（−ＳＯ_２−アリール）、スルホンアミド（−ＳＯ_２−ＮＨ_２、−ＳＯ_２ＮＹ_２（式中、Ｙは独立してＨ、アリーリル（ａｒｌｙｌ）またはアルキルである）、ホスホノ（−Ｐ（Ｏ）（ＯＨ）_２）、ホスホナト（−Ｐ（Ｏ）（Ｏ⁻）_２）、ホスフィナト（−Ｐ（Ｏ）（Ｏ⁻））、ホスホ（−ＰＯ_２）、ホスフィノ（−−ＰＨ_２）、ポリアルキルエーテル（−［（ＣＨ_２）_ｎＯ］_ｍ）、ホスフェート、リン酸エステル［−ＯＰ（Ｏ）（ＯＲ）_２、式中、Ｒ＝Ｈ、メチルまたは他のアルキルである］、アミノ酸または生理的ｐＨで正または負電荷を有することが予想される他の部分を組み込んだ基、およびそれらの組み合わせからなる群より独立して選択され；
ここで、Ｒ^７は下記ではない：

。 In still other embodiments, the 15-PGDH inhibitor can include a compound having formula (III) as well as a pharmaceutically acceptable salt thereof:

Where n = 0-2;
X ⁶ is N or CR ^c ;
X ⁷ is N or C;
R ¹ is — (CH ₂ ) n ₁ CH ₃ (n ₁ = 0-7),

Where n ₂ = 0-6 and X is one of the following:
CF _y H _z (y + z = 3), CCl _y H _z (y + z = 3), OH, OAc, OMe, R ⁷¹ , OR ⁷² , CN, N (R ⁷³ ) ₂ ,

(N ₄ = 0-5)
Selected from the group consisting of branched or straight chain alkyls including:
R ⁵ is selected from the group consisting of H, OH, Cl, F, NH ₂ , N (R ⁷⁶ ) ₂ , and OR ⁷⁷ _;
Each R ⁷ can independently be one of the following:

Each ^{_{R 8, R 9, R 10}} , R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19, R 20, R 21, R 22, R 23, R ^{_{24, R 25, R 26,}} R 27a, R 27b, R 28, R 29, R 30, R 31, R 32, R 33, R 34, R 35, R 36, R 37, R 38, R 39, R ⁴⁰ _, R ⁴¹ _, R ⁴² _, R ⁴³ _, R ⁴⁴ _, R ⁴⁵ _, R ⁴⁶ _, R ⁴⁷ _, R ⁷¹ _, R ⁷² _, R ⁷³ _, R ⁷⁴ _, R ⁷⁶ , R ⁷⁷ , R ^c , and R ^d are the same or different, and, Haitai containing hydrogen, substituted or unsubstituted _C 1 _{-C 24 alkyl,} C 2 _{-C 24 alkenyl,} C 2 _{-C 24 alkynyl,} C 3 _{-C 20} aryl, a 5-6 ring atoms Rocycloalkenyl, wherein 1-3 ring atoms are independent of N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O, and S Heteroaryl or heterocyclyl containing 5-14 ring atoms, wherein 1-6 ring atoms are N, NH, N (C ₁ -C ₃ alkyl), O, and S C ₆ -C ₂₄ alkaryl, C ₆ -C ₂₄ aralkyl, halo, silyl, hydroxyl, sulfhydryl, C ₁ -C ₂₄ alkoxy, C ₂ -C ₂₄ alkenyloxy, C ₂ -C _{24 alkynyloxy,} C 5 _{-C 20} aryloxy, acyl _(e.g., C 2 _{-C 24} alkylcarbonyl (--CO- alkyl) and _C 6 _{-C 20} arylcarbonyl (-CO- aryl ), Acyloxy (-O- _acyl), C 2 _{-C 24} alkoxycarbonyl (- (CO) -O- _alkyl), C 6 _{-C 20} aryloxycarbonyl (- (CO) -O- aryl), _{C 2} - C ₂₄ alkyl carbonate (—O— (CO) —O-alkyl), C ₆ -C ₂₀ aryl carbonate (—O— (CO) —O-aryl), carboxy (—COOH), carboxylate (—COO ^-), carbamoyl _{(- (CO) - NH 2} ), C 1 -C 24 alkyl - carbamoyl _{(- (CO) -NH (C} 1 -C 24 alkyl)), arylcarbamoyl (- (CO) -NH- aryl), thiocarbamoyl _{(- (CS) -NH 2)} , carbamide _{(-NH- (CO) -NH 2)} , cyano (-CN), isocyano ^(-N + C ^-), shea Preparative (-O-CN), isocyanato ^{(-O-N + = C -} ), isothiocyanato (-S-CN), azido ^{(-N = N + = N -} ), formyl (- (CO) - H ), thioformyl (- (CS) - H) , amino _{(--NH 2), C 1 -C} 24 _alkylamino, C 5 _{-C 20 arylamino,} C 2 _{-C 24} alkylamido (-NH- ( CO) - _alkyl), C 6 _{-C 20} aryl amide (-NH- (CO) - aryl), sulfonamide _{(-SO 2 N (R) 2} , wherein, R is independently H, alkyl, aryl, or Is heteroaryl), imino (—CR═NH, where R is hydrogen, C ₁ -C ₂₄ alkyl, C ₅ -C ₂₀ aryl, C ₆ -C ₂₄ alkaryl, C ₆ -C ₂₄ aralkyl, etc. ), Alkylimino ( CR = N (alkyl), where R = hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (—CR = N (aryl), where R = hydrogen, alkyl, aryl, alkaryl) ), Nitro (—NO ₂ ), nitroso (—NO), sulfo (—SO ₂ —OH), sulfonate (—SO ₂ —O ⁻ ), C ₁ -C ₂₄ alkylsulfanyl (—S-alkyl). ; also referred to as "alkylthio"), arylsulfanyl (-S- aryl; also termed _"arylthio"), C 1 _{-C 24} alkylsulfinyl (- (SO) - _alkyl), C 5 _{-C 20} arylsulfinyl (- (SO ) - _aryl), C 1 _{-C 24} alkylsulfonyl (-SO ₂ - _alkyl), C 5 _{-C 20} arylsulfonyl ( SO ₂ - aryl), sulfonamide _{(-SO 2 -NH 2, -SO 2} NY 2 ( in the formula, Y is independently H, Aririru (Arlyl) or alkyl), phosphono (-P (O) ( OH) ₂ ), phosphonate (—P (O) (O ⁻ ) ₂ ), phosphinate (—P (O) (O ⁻ )), phospho (—PO ₂ ), phosphino (—PH ₂ ), polyalkyl ether (— [(CH ₂ ) _n O] _m ), phosphate, phosphate ester [—OP (O) (OR) ₂ , where R = H, methyl or other alkyl], amino acid or physiological pH Independently selected from the group consisting of groups incorporating other moieties expected to have a positive or negative charge at and combinations thereof;
Where R ⁷ is not:

.

。 Examples of 15-PGDH inhibitors having formula (I), (II), or (III) can include the following compounds as well as pharmaceutically acceptable salts thereof:

.

。 Other examples of 15-PGDH inhibitors having the formula (I), (II), or (III) include the following compounds as well as pharmaceutically acceptable salts thereof:

.

。 In some embodiments, the 15-PGDH inhibitor having the formula (I), (II), or (III) is not a compound having the formula: and pharmaceutically acceptable salts thereof:

.

In still other embodiments, at least one of R ⁸ -R ⁷⁶ is independently a group that improves water solubility, such as phosphate ester (—OPO ₃ H ₂ ), phosphate ester (—OPO ₃ H). ₂ ) can be a phenyl ring linked to 1), a phenyl ring substituted with one or more methoxyethoxy groups, or a morpholine, or an aryl or heteroaryl ring substituted with such a group.

In certain embodiments, ia) Vaco503 expressing a 15-PGDH luciferase fusion construct at 2.5 μM concentration to a luciferase output level greater than 70 (using a scale where a value of 100 indicates doubling of reporter output relative to baseline). Stimulate the reporter cell line; ia) At 2.5 μM concentration, stimulate the V9m reporter cell line expressing the 15-PGDH luciferase fusion construct to a luciferase output level greater than 75; iii) At the 7.5 μM concentration, stimulate 70 Stimulate the LS174T reporter cell line expressing the 15-PGDH luciferase fusion construct to luciferase output levels above; and iva) TK-renilla at levels above 7.5 at 7.5 μM concentration Negative control V9m cell lines not activate expressing Ke luciferase reporter; inhibiting the enzymatic activity of recombinant 15-PGDH protein and va) _{IC 50} of less than 1 [mu] M, Formula (V), at and _{(V 1)} A 15-PGDH inhibitor can be selected.

In other embodiments, the 15-PGDH inhibitor ib) stimulates a Vaco503 reporter cell line expressing a 15-PGDH luciferase fusion construct to increase luciferase output at 2.5 μM concentration; iib) 2. Stimulate V9m reporter cell line expressing 15-PGDH luciferase fusion construct to increase luciferase output at 5 μM concentration; iii) At 15 μM concentration, 15-PGDH luciferase fusion construct to increase luciferase output Iv174) expressing TK-Renilla luciferase reporter to a luciferase level greater than 20% above background at 7.5 μM concentration That negative control V9m cell lines without activation; in and vb) _{IC 50} of less than 1 [mu] M, inhibit the enzymatic activity of recombinant 15-PGDH protein.

In other embodiments, 15-PGDH inhibitors, in recombinant 15-PGDH concentration of about 5nM~ about 10 nM, with _{an IC 50} of less than 1 [mu] M, preferably with _{an IC 50} of less than 250 nM, more preferably less than 50nM with an IC _50, and more preferably with _{an IC 50} of less than 10 nM, more preferably with _{an IC 50} of less than 5 nM, it can inhibit the enzymatic activity of recombinant 15-PGDH.

  In other embodiments, 15-PGDH inhibitors can increase cellular levels of PGE-2 following stimulation with a suitable agent of A459 cells, such as IL1-β.

The 15-PGDH inhibitors described herein may be used to prevent or treat diseases associated with 15-PGDH and / or decreased prostaglandin levels and / or reduce prostaglandin levels in a subject. Can be used when it is desirable to increase. For example, as described above, prostaglandins are known to play an important role in hair growth. Specifically, the internal storage of various types (A ₂ , F _2a , E ₂ ) of prostaglandins in various compartments of the hair follicles or their adjacent skin environment maintains and increases hair density. (Columbe L et. Al, 2007, Exp. Dermatol, 16 (9), 762-9). 15-PGDH involved in prostaglandin degradation is present in hair follicle dermal papilla and has been reported to inactivate prostaglandins, especially PGF _2a and PGE ₂ , causing scalp damage and alopecia (Michelet J F et. Al., 2008, Exp. Dermatol, 17 (10), 821-8). Thus, the compounds described herein having inhibitory or inhibitory activity against 15-PGDH that degrades prostaglandins can improve scalp damage, prevent alopecia, and promote hair growth. It can be used in a pharmaceutical composition for preventing alopecia and promoting hair growth.

  In other embodiments, the 15-PGDH inhibitors described herein are in pharmaceutical compositions for promoting and / or inducing and / or stimulating pigmentation of the skin and / or skin appendages, and / or Alternatively, it can be used as an agent for preventing and / or limiting depigmentation and / or whitening of the skin and / or skin appendages, in particular as an agent for preventing and / or limiting shirring.

  In some embodiments, the 15-PGDH inhibitor promotes and / or stimulates skin pigmentation and / or hair growth, inhibits hair loss, and / or skin damage or inflammation, eg, physical or chemical To treat skin damage caused by irritants and / or UV-exposures, it can be applied to the skin of a subject, for example, in topical application.

  In still other embodiments, the 15-PGDH inhibitors described herein prevent or treat cardiovascular and / or circulatory disorders such as Raynaud's disease, Buerger's disease, diabetic neuropathy, and pulmonary arterial hypertension. Can be used in a pharmaceutical composition. Prostaglandins, including prostaglandin homologs produced in the body, maintain the proper function of the vascular wall, especially contribute to vasodilation for blood flow, prevent platelet aggregation, and surround the vascular wall It is known to regulate smooth muscle proliferation (Yan. Cheng et. Al., 2006, J. Clin., Invest). In addition, inhibition of prostaglandin production or loss of their activity causes dysfunction of endothelium within the vessel wall, platelet aggregation and dysfunction of cellular mechanisms in smooth muscle. In particular, prostaglandin production in blood vessels has been shown to decrease in hypertensive patients, including pulmonary arterial hypertension.

  In other embodiments, the 15-PGDH inhibitors described herein are oral, intestinal, and / or gastrointestinal injuries or diseases, or inflammatory bowel diseases such as oral ulcers, periodontal disease, gastritis, colitis It can be used in pharmaceutical compositions for the prevention or treatment of ulcerative colitis and gastric ulcers. Gastritis and gastric ulcers, which are representative of gastrointestinal diseases, are defined as conditions in which the gastrointestinal mucosa is digested by gastric acid and ulcers are formed. Generally, in the stomach wall consisting of mucosa, submucosa, muscle layer and serosa, gastric ulcer further damages the submucosa and muscle layer, while gastritis damages only the mucosa. The prevalence of gastritis and gastric ulcers is relatively high, but the reason is not yet clear. To date, they are known to be caused by an imbalance between attack and defense factors, i.e. increased attack factors, e.g. increased gastric acid or pepsin secretion, or decreased defense factors, e.g. gastric mucosal Structural or morphological defects, decreased mucus and bicarbonate secretion, decreased prostaglandin production, and the like.

  Currently available treatments for gastritis and gastric ulcers include various drugs to strengthen defense factors, such as antacids (which do not affect gastric acid secretion but neutralize already produced gastric acid A gastric acid secretion inhibitor, a prostaglandin secretion promoter, and a coating for the stomach wall. In particular, prostaglandins are known to be essential for maintaining mechanisms for protecting and protecting the gastric mucosa (Wallace J L., 2008, Physiol Rev., 88 (4), 1547- 65, S. J. Konturek et al., 2005, Journal of Physiology and Pharmacology, 56 (5)). In view of the above, the 15-PGDH inhibitors described herein exhibit inhibitory or inhibitory activity against 15-PGDH, which degrades prostaglandins that protect the gastric mucosa, so that they are gastrointestinal diseases, In particular, it can be effective in preventing or treating gastritis and gastric ulcers.

  Moreover, 15-PGDH inhibitors would be expected to protect against other forms of intestinal damage, including toxicity from radiation, toxicity from chemotherapy, and chemotherapy-induced mucositis.

In the kidney, prostaglandins can act to regulate renal blood flow and control urine formation by both renal vascular and tubule effects. In clinical studies, PGE ₁ improves creatinine clearance in patients with chronic kidney disease, prevents graft rejection and cyclosporine toxicity in kidney transplant patients, and urinary albumin excretion rates in patients with diabetic nephropathy and It has been used to reduce N-acetyl-β-D-glucosaminidase levels (see Porter, Am., 1989, J. Cardiol., 64: 22E-26E). In addition, US Pat. No. 5,807,895 discloses a method for preventing renal dysfunction by intravenous administration of prostaglandins such as PGE ₁ , PGE ₂ and PGI ₂ . Furthermore, it has been reported that prostaglandins function as vasodilators in the kidneys and thus result in impaired renal function due to inhibition of prostaglandin production in the kidneys (Hao. CM, 2008, Annu Rev Physiol, 70). 357.about.77).

  Therefore, the 15-PGDH inhibitors described herein have inhibitory or inhibitory activity against 15-PGDH that degrades prostaglandins and are effective in preventing or treating renal diseases associated with renal dysfunction. obtain.

  The term “renal dysfunction” as used herein includes the following indications: below normal creatinine clearance, below normal free water clearance, above normal blood urea, nitrogen, potassium and / or creatinine levels Altered activity of kidney enzymes such as γ-glutamyl synthetase, alanine phosphatidase, N-acetyl-β-D-glucosaminidase, or β-w-microglobulin; and an increase over normal levels of macroalbuminuria.

Prostaglandins including PGE ₁ , PGE ₂ and PGF _2a have also been shown to stimulate bone resorption and bone formation and increase bone volume and strength (H. Kawaguchi et al., Clinical Orthop. Rel. Res., 313, 1995; J. Keller et al., Eur. Jr. Exp. Musculozelal Res., 1, 1992, 8692). As mentioned above, considering that 15-PGDH inhibits the activity of prostaglandins, the inhibition of 15-PGDH activity results in the promotion of bone resorption and bone formation inhibited by 15-PGDH. obtain. Thus, the 15-PGDH inhibitors described herein may be effective in promoting bone resorption and bone formation by inhibiting 15-PGDH activity. 15-PGDH inhibitors also increase bone density, treat osteoporosis, promote fracture healing, or promote healing after bone surgery or joint replacement, or bone implants, artificial implants, dental implants and transplants It can be used to promote bone healing against bone.

  In yet other embodiments, the 15-PGDH inhibitors described herein may be effective in treating cancers that express 15-PGDH. Inhibition of 15-PGDH can inhibit the growth, proliferation, and metastasis of cancers that express 15-PGDH.

In yet other embodiments, the 15-PGDH inhibitors described herein can be effective in wound healing. Among various prostaglandins, PGE ₂ is known to function as a mediator for wound healing. Therefore, if the skin is damaged by wounds or burns, by inhibition of 15-PGDH activity, therapeutic effect of PGE ₂ wounds or burns can be generated.

  In addition, as noted above, increased prostaglandin levels have been shown to stimulate signaling through the Wnt signaling pathway through increased β-catenin-mediated transcriptional activity. Wnt signaling is known to be an important pathway used by tissue stem cells. Thus, the 15-PGDH inhibitors described herein increase the number of tissue stem cells for purposes that would include promoting tissue regeneration or repair in organs including the liver, colon, and bone marrow. Can be used to In addition, the 15-PGDH inhibitors described herein can be added to additional organs (brain, eyes, cornea, retina, lung, heart, stomach, small intestine, pancreas, pancreatic β-cells, kidney, bone, cartilage, It can be used to promote tissue regeneration or repair in (including but not limited to peripheral nerves).

  Symptomatic conditions, traumatic disorders, chronic medical conditions, medical interventions that cause or are associated with the need for tissue damage and repair, and are therefore suitable for treatment or remission using the methods described herein , Or other medical conditions include, but are not limited to: acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusion, arteries Sclerosis, articular cartilage defect, aseptic systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, fracture, fracture, cerebral edema, cerebral hypoperfusion, Buerger's disease, burns, cancer, cardiovascular disease, Cartilage injury, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic infection, chronic mesenteric ischemia, lameness, congestive heart failure, connective tissue injury, contusion, coronary artery Disease (CAD), severe ischemic limb (CLI), Crohn's disease, deep vein thrombosis, deep wound, delayed ulcer healing, delayed wound healing, diabetes (type I and type II), diabetes, diabetic neuropathy, diabetes Induced ischemia, disseminated intravascular coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, frostbite, hereditary hemorrhagic telangiectatic ischemic vascular disease, hyperoxia injury, hypoxia, Inflammation, inflammatory bowel disease, inflammatory disease, injured tendon, intermittent claudication, intestinal ischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic kidney disease, imaginary Blood vascular disease, ischemic-reperfusion injury, laceration, left main coronary artery lesion, ischemic limb, lower limb ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease Peripheral arterial disease (PAD), peripheral arterial disease, peripheral ischemia, peripheral Neuropathy, peripheral vascular disease, precancer, pulmonary edema, pulmonary embolism, remodeling disorder, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcer, solid organ transplantation, spinal cord injury, stroke, subchondral bone cyst, Thrombosis, thrombotic cerebral ischemia, tissue ischemia, transient cerebral ischemic attack (TIA), traumatic brain injury, ulcerative colitis, renal vascular disease, vascular inflammatory condition, von Hippel-Lindau syndrome, and A wound to a tissue or organ.

  Genetic disorders, symptomatic conditions, traumatic disorders, chronic medical conditions, medical conditions that cause or are associated with the need for tissue damage and repair, suitable for treatment or remission using the methods of the invention Other illustrative examples of interventions or other medical conditions include surgery, chemotherapy, radiation therapy, or ischemia due to cell, tissue, or organ transplant or graft.

  In various embodiments, the method of the invention comprises cerebrovascular ischemia, myocardial ischemia, ischemic limb (CLI), myocardial ischemia (especially chronic myocardial ischemia), ischemic cardiomyopathy, cerebrovascular ischemia, renal ischemia. It is suitable for treating pulmonary ischemia, intestinal ischemia, and the like.

  In some embodiments, ischemia is associated with at least one of the following: acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusion, artery Sclerosis, articular cartilage defect, aseptic systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, fracture, fracture, cerebral edema, hypoperfusion, Buerger disease, burn, cancer, cardiovascular disease, cartilage injury, Cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic infection, chronic mesenteric ischemia, lameness, congestive heart failure, connective tissue injury, contusion, coronary artery disease (CAD), severe ischemia Limb (CLI), Crohn's disease, deep vein thrombosis, deep wound, delayed ulcer healing, delayed wound healing, diabetes (type I and type II), diabetic neuropathy, diabetes-induced ischemia, disseminated intravascular coagulation DIC), embolic cerebral ischemia, graft-versus-host disease, hereditary hemorrhagic telangiectatic ischemic vascular disease, hyperoxia injury, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injured tendon, Intermittent claudication, intestinal ischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic kidney disease, ischemic vascular disease, ischemic-reperfusion injury, laceration, Left main coronary artery lesion, ischemic limb, lower limb ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease, peripheral arterial disease (PAD), peripheral arterial disease, peripheral Ischemia, peripheral neuropathy, peripheral vascular disease, precancer, pulmonary edema, pulmonary embolism, remodeling disorder, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcer, solid organ transplantation, spinal cord injury, stroke, Subchondral bone cyst, thrombosis, thrombotic cerebral ischemia, tissue ischemia, transient brain Blood attack (TIA), traumatic brain injury, ulcerative colitis, vascular diseases of the kidney, vascular inflammatory states, von Hippel-Lindau syndrome, and tissue or wound against organ.

  In some embodiments, the 15-PGDH inhibitor increases the fitness or transplant of the stem cell preparation as a donor graft to a subject's hematopoietic stem cell, eg, peripheral blood hematopoietic stem cell or umbilical cord stem cell preparation. Can be administered to reduce the number of cord blood units required.

  Hematopoietic stem cells are the bone marrow (eg monocytes and macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes / platelets, dendritic cells) and lymphoid lineages (eg T-cells, B- Cells, NK-cells), multipotent stem cells that give rise to all blood cell types of an organism, including others known in the art (Fei, R. et al., US Pat. No. 5,635,35). McGlave et al., US Pat. No. 5,460,964; Simmons, P. et al., US Pat. No. 5,677,136; Tsukamoto et al., US Pat. No. 5,750,397; Schwartz et al., US Pat. No. 5,759,793; DiGuisto et al., US Pat. No. 5,681,599; Tsukamoto et al., US Pat. No. 5,716,827). Hematopoietic stem cells (HSCs) give rise to committed hematopoietic progenitor cells (HPCs) that can generate the entire repertoire of mature blood cells over the life of the organism.

Hematopoietic stem cells and hematopoietic progenitor cells, unless otherwise stated, can generally refer to cells or populations described herein as hematopoietic stem cells and identified by the presence of the antigen marker CD34 (CD34 ⁺ ). In some embodiments, hematopoietic stem cells can be identified by the presence of the antigen marker CD34 and the absence of a cell line (lin) marker, and are thus characterized as CD34 ⁺ / lin ⁻ cells.

  The hematopoietic stem cells used in the methods described herein can be obtained from any suitable source of hematopoietic stem and progenitor cells, as a highly purified population of hematopoietic stem cells, or from about 0.01% to about 100% Can be provided as a composition comprising hematopoietic stem cells. For example, the hematopoietic stem cells are a composition, such as unfractionated bone marrow (where hematopoietic stem cells comprise less than about 1% bone marrow cell population), umbilical cord blood, placental blood, placenta, fetal blood, fetal liver, fetus It can be provided in spleen, walton jelly, or mobilized peripheral blood.

  Suitable hematopoietic stem cell sources can be isolated or obtained from a body organ containing cells of hematopoietic origin. Isolated cells can include cells that have been removed from their original environment. For example, a cell is isolated if it is separated from some or all of the components that normally accompany it in its native state. For example, an “isolated cell population”, “isolated cell source” or “isolated hematopoietic stem cell” and the like are used herein from the natural cell environment of one or more cells, Shows in vitro or ex vivo separation from the association with other components of the tissue or organ, ie it is not significantly associated with in vivo material.

  Hematopoietic stem cells can be obtained or isolated from adult bone marrow, including femur, hipbone, ribs, sternum, and other bones. Bone marrow aspiration fluid containing hematopoietic stem cells can be obtained or isolated from the buttocks using a needle and syringe. Other hematopoietic stem cell sources include umbilical cord blood, placental blood, mobilized peripheral blood, Walton jelly, placenta, fetal blood, fetal liver, or fetal spleen. In certain embodiments, mobilizing stem and progenitor cells in a donor may be required to collect a sufficient amount of hematopoietic stem cells for use in therapeutic applications.

  “Hematopoietic stem cell mobilization” refers to the release of stem cells from the bone marrow into the peripheral blood circulation for the purpose of leukocyte removal prior to stem cell transplantation. By increasing the number of stem cells collected from the donor, the number of stem cells that can be used for therapeutic applications can be significantly improved. Hematopoietic growth factors such as granulocyte colony stimulating factor (G-CSF) or chemotherapeutic drugs are often used to stimulate mobilization. Commercially available stem cell mobilization drugs exist and can be used in combination with G-CSF to mobilize a sufficient amount of hematopoietic stem and progenitor cells for transplantation into a subject. For example, G-CSF and Mozobil (Genzyme Corporation) can be administered to a donor to collect a sufficient number of hematopoietic cells for transplantation. Other methods of mobilizing hematopoietic stem cells will be apparent to those skilled in the art.

  In some embodiments, hematopoietic stem and progenitor cells (HSPC) are obtained from umbilical cord blood. Umbilical cord blood is a technique known in the art (see, eg, US Pat. Nos. 7,147,626 and 7,131,958, hereby incorporated by reference for such methods). Incorporated).

  In one embodiment, HSPC can be obtained from a pluripotent stem cell source, such as induced pluripotent stem cells (iPSC) and embryonic stem cells (ESC). As used herein, the term “induced pluripotent stem cell” or “iPSC” refers to a non-pluripotent cell that has been reprogrammed to a pluripotent state. As soon as the subject's cells are reprogrammed to a pluripotent state, the cells can be programmed into the desired cell type, eg, hematopoietic stem or progenitor cells. As used herein, the term “reprogramming” refers to a method of increasing the potency of a cell to a more undifferentiated state. As used herein, the term “programming” refers to a method of decreasing the potency of a cell or differentiating a cell to a more differentiated state.

  In some embodiments, hematopoietic stem cells can be administered or contacted with one or more 15-PGDH inhibitors described herein ex vivo to provide a therapeutic composition Is done. In one embodiment, the therapeutic composition can include a population of hematopoietic stem cells treated with one or more 15-PGDH inhibitors ex vivo. In certain embodiments, the therapeutic composition comprising enhanced HSPC is whole bone marrow, umbilical cord blood, or mobilized peripheral blood.

  In certain embodiments, the therapeutic composition comprises a population of cells, wherein the population of cells is about 95% to about 100% hematopoietic stem cells. The invention may be used, in part, for the treatment of highly purified hematopoietic stem cells, eg, a composition comprising a population of cells wherein the cells comprise about 95% hematopoietic stem cells, which may improve the efficiency of stem cell therapy. Contemplate. Currently, the transplantation methods performed typically use an unfractionated mixture of cells, where hematopoietic stem cells account for less than 1% of the total cell population.

  In some embodiments, the therapeutic composition comprises a population of cells, wherein the population of cells is about 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15% , 20%, 25%, or less than 30% hematopoietic stem cells. The population of cells, in some embodiments, is less than about 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 25%, or 30% hematopoietic Contains stem cells. In other embodiments, the population of cells is about 0.1% to about 1%, about 1% to about 3%, about 3% to about 5%, about 10% -15%, about 15% -20% About 20% -25%, about 25% -30%, about 30% -35%, about 35% -40%, about 40% -45%, about 45% -50%, about 60% -70%, About 70% -80%, about 80% -90%, about 90% -95%, or about 95% to about 100% of hematopoietic stem cells.

  The hematopoietic stem cells in the therapeutic composition of the present invention may be autologous / self-sourced (“self”) or non-autologous (“non-self”, eg, allogeneic, syngeneic or xenogeneic) to the subject to which the therapeutic composition is administered. It can be. “Autologous” as used herein refers to cells from the same subject. “Homologous” refers herein to cells of the same species that are genetically different from the comparative cells. “Syngeneic” as used herein refers to cells of a different subject that are genetically identical to a comparative cell. “Heterologous” as used herein refers to a cell of a different species than the comparative cell.

Hematopoietic stem cells for use in the methods of the present invention can be derived from bone marrow aspirate, umbilical cord blood, or mobilized peripheral blood (mobilized leukocyte removal product), mature hematopoietic cells such as T cells, B cells, NK cells, Dendritic cells, monocytes, granulocytes, red blood cells, and their committed precursors can be depleted. Mature, lineage committed cells are depleted by immunodepletion, for example by labeling a solid substrate with an antibody that binds to a panel of so-called “lineage” antigens: CD2, CD3, CD11b, CD14, CD15, CD16, CD79, CD56, CD123, and CD235a. Subsequent steps to further purify the population of cells can be performed, in which case a substrate labeled with an antibody that binds CD34 ⁺ antigen is used to isolate primitive hematopoietic stem cells. Kits for purifying stem and progenitor cells from various cell sources are commercially available, and in certain embodiments, these kits are suitable for use with the methods described herein.

In one embodiment, the amount of hematopoietic stem cells in the therapeutic composition is at least 0.1 × 10 ⁵ cells, at least 0.5 × 10 ⁵ cells, at least 1 × 10 ⁵ cells, at least 5 × 10 ⁵ cells, at least 10 × 10 ⁵ cells, at least 0.5 × 10 ⁶ cells, at least 0.75 × 10 ⁶ cells, at least 1 × 10 ⁶ cells, at least 1.25 × 10 ⁶ cells, at least 1.5 × 10 ⁶ cells, at least 1.75 × 10 ⁶ cells, at least 2 × 10 ⁶ cells, at least 2.5 × 10 ⁶ cells, at least 3 × 10 ⁶ cells, at least 4 × 10 ⁶ cells, at least 5 × 10 ⁶ cells, at least 10 × 10 ⁶ Cells, at least 15 × 10 ⁶ cells, at least 20 × 10 ⁶ cells, at least 25 × 10 ⁶ cells, or at least 30 × 10 ⁶ cells.

In one embodiment, the amount of hematopoietic stem cells in the therapeutic composition is the amount of HSPC in a partial or single band of blood, or a body weight of at least 0.1 × 10 ⁵ cells / kg, at least 0.5 ×. Body weight of 10 ⁵ cells / kg, body weight of at least 1 × 10 ⁵ cells / kg, body weight of at least 5 × 10 ⁵ cells / kg, body weight of at least 10 × 10 ⁵ cells / kg, body weight of at least 0.5 × 10 ⁶ cells / kg kg body weight, at least 0.75 × 10 ⁶ cells / kg, at least 1 × 10 ⁶ cells / kg, at least 1.25 × 10 ⁶ cells / kg, at least 1.5 × 10 ⁶ cells / kg kg of body weight, body weight of at least 1.75 × 10 ⁶ cells / kg body weight of at least 2 × 10 ⁶ cells / kg body weight of at least 2.5 × 10 ⁶ cells / kg, at least 3 × 10 ⁶ cells / k Of body weight, at least 4 × 10 ⁶ cells / kg body weight, body weight of at least 5 × 10 ⁶ cells / kg body weight of at least 10 × 10 ⁶ cells / kg, of at least 15 × 10 ⁶ cells / kg body weight, at least 20 × A body weight of 10 ⁶ cells / kg, a body weight of at least 25 × 10 ⁶ cells / kg, or a body weight of at least 30 × 10 ⁶ cells / kg.

  Preparations of hematopoietic stem cells administered with one or more 15-PGDH inhibitors and / or therapeutic compositions comprising hematopoietic stem cells and one or more 15-PGDH inhibitors may improve hematopoietic stem cell transplantation and Improve angiogenic response in ischemic tissue in the treatment of tissue damaged by blood or ischemia, and reduce further damage to ischemic tissue and / or repair damage to ischemic tissue by cell mobilization Can be used to improve tissue regeneration at the ischemic site, reduce ischemic tissue necrosis or apoptosis, and / or increase cell survival at the ischemic site. In certain embodiments, a preparation of hematopoietic stem cells treated with a 15-PGDH inhibitor and / or a therapeutic composition of 15-PGDH inhibitor and hematopoietic stem cells is used in a subject in need of hematopoietic reconstitution, eg, myeloablative Useful for subjects who have received or are scheduled to receive therapy.

  Preparations of hematopoietic stem cells treated with a 15-PGDH inhibitor and / or subjects that can be treated with a therapeutic composition of 15-PGDH inhibitors and hematopoietic stem cells include various types of leukemia, anemia, lymphoma, myeloma. , Immune deficiency disorders, and subjects with or diagnosed with solid tumors. Subjects also include humans who are candidates for stem cell transplantation or bone marrow transplantation during the course of therapy, for example for a malignancy or a component of gene therapy. Subjects also include individuals or animals that provide stem cells or bone marrow for allogeneic transplantation. In certain embodiments, the subject may have received myeloablative radiation therapy or chemotherapy, or may have experienced acute radiation or chemical invasion, resulting in bone marrow destruction. In certain embodiments, for example, during various cancer treatments, the subject may have received radiation therapy or chemotherapy. A typical subject includes an abnormal amount (lower or higher amount than a “normal” or “healthy” subject) of one or more physiology that can be modulated by an agent or stem cell or bone marrow transplant. And animals that exhibit active activity.

  A subject that can be treated with a preparation of hematopoietic stem cells treated with a 15-PGDH inhibitor and / or a therapeutic composition of 15-PGDH inhibitors and hematopoietic stem cells may also be treated with chemotherapy or radiation therapy for cancer. Subjects who are receiving, as well as subjects suffering from (eg suffering from) the following: non-malignant blood disorders, especially immunodeficiencies (eg SCID, Fanconi anemia, severe aplastic anemia, or congenital) Abnormal hemoglobinosis, or metabolic storage diseases such as Hurler's disease, Hunter's disease, mannose disease, etc.) or cancer, especially hematological malignancies such as acute leukemia, chronic leukemia (bone marrow or lymph), lymphoma (Hodgkin or non-Hodgkin), Multiple myeloma, myelodysplastic syndrome, or non-blood cancer, such as solid tumors (breast cancer, ovarian cancer, brain cancer, prostate cancer, Including cancer, colon cancer, skin cancer, liver cancer, or pancreatic cancer).

  Subjects also include those suffering from aplastic anemia, immune disorders (severe combined immunodeficiency syndrome or lupus), myelodysplasia, thalassemia, sickle cell disease or Wiscott Aldrich syndrome obtain. In some embodiments, the subject is treated with another primary treatment, eg, radiation therapy, chemotherapy, or a myelosuppressant such as zidovadine, chloramphenic, or gangciclovir. Suffer from disorders that are the result of undesirable side effects or complications. Such disorders include neutropenia, anemia, thrombocytopenia, and immune dysfunction. Other subjects may have a disorder caused by an infection that causes damage to bone marrow stem or progenitor cells (eg, viral infection, bacterial infection or fungal infection).

  In addition, subjects suffering from the following medical conditions may also benefit from preparations of hematopoietic stem cells treated with 15-PGDH inhibitors and / or treatment using 15-PGDH inhibitors and therapeutic compositions of hematopoietic stem cells: Can: lymphopenia, lymphatic leakage, lymphatic stasis, erythrocytopenia, erythrodegenerative disorder, erythrocytopenia, leukoblastosis; erythrocyte decay, Mediterranean anemia, spinal dysplasia, bone marrow fiber Disease, thrombocytopenia, disseminated intravascular coagulation (DIC), immune (autoimmune) thrombocytopenic purpura (ITP), HIV-induced ITP, myelodysplasia; thrombocytosis, thrombocytosis, congenital Neutropenia (eg, Costman syndrome and Schwakman diamond syndrome), neoplastic-related neutropenia, childhood and adult cycles Neutropenia; post-infectious neutropenia; myelodysplastic syndrome; neutropenia associated with chemotherapy and radiation therapy; chronic granulomatous Disease; mucopolysaccharidosis; diamond blackfan anemia; sickle cell disease; or severe beta thalassemia.

  In other embodiments, a preparation of hematopoietic stem cells treated with a 15-PGDH inhibitor and / or a therapeutic composition of 15-PGDH inhibitor and hematopoietic stem cells treats ischemic tissue or is associated with tissue ischemia One or more symptoms of, for example, but not limited to, dysfunction or loss of organ function (including but not limited to dysfunction or loss of brain, kidney, or heart function), muscle spasm, lameness, numbness, It can be used in cell therapy to treat or ameliorate tingling, weakness, pain, reduced wound healing, inflammation, skin discoloration, and gangrene.

  In one embodiment, the subject exhibits at least one symptom of ischemic tissue or tissue damaged by ischemia. In certain embodiments, the subject has or is at risk for ischemic tissue or tissue damaged by ischemia, such as diabetes, peripheral vascular disease, obstructive thrombovasculitis, vasculitis, cardiovascular A subject having a disease, coronary artery disease or heart failure, or cerebrovascular disease, cardiovascular disease, or cerebrovascular disease.

  The method of causing or associated with or increasing the risk of ischemia in a subject or causing the subject to present one or more symptoms of ischemia, and thus the methods described herein Illustrative examples of hereditary disorders, symptomatic conditions, traumatic disorders, chronic conditions, medical interventions, or other conditions that are suitable for treatment or remission with the following include, but are not limited to: Acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusion, arteriosclerosis, articular cartilage defect, aseptic systemic inflammation, atherosclerotic heart Vascular disease, autoimmune disease, fracture, fracture, cerebral edema, cerebral hypoperfusion, Buerger's disease, burns, cancer, cardiovascular disease, cartilage damage, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy Inducible Neuropathy, chronic infection, chronic mesenteric ischemia, lameness, congestive heart failure, connective tissue injury, contusion, coronary artery disease (CAD), severe ischemic limb (CLI), Crohn's disease, deep vein thrombosis, deep wound, delayed Ulcer healing, delayed wound healing, diabetes (type I and type II), diabetic neuropathy, diabetes-induced ischemia, disseminated intravascular coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, frostbite , Hereditary hemorrhagic telangiectasia ischemic vascular disease, hyperoxia injury, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injured tendon, intermittent claudication, intestinal ischemia, ischemia, ischemic brain Disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic renal disease, ischemic vascular disease, ischemic-reperfusion injury, laceration, left coronary artery main lesion, ischemic limb, lower limb ischemia, Myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis Osteosarcoma, Parkinson's disease, peripheral arterial disease (PAD), peripheral arterial disease, peripheral ischemia, peripheral neuropathy, peripheral vascular disease, precancer, lung edema, pulmonary embolism, remodeling disorder, renal ischemia, retinal ischemia Retinopathy, sepsis, skin ulcer, solid organ transplantation, spinal cord injury, stroke, subchondral bone cyst, thrombosis, thrombotic cerebral ischemia, tissue ischemia, transient ischemic attack (TIA), traumatic Brain injury, ulcerative colitis, renal vascular disease, vascular inflammatory conditions, von Hippel-Lindau syndrome, and wounds to tissues or organs.

  In a subject, causing or associated with ischemia, or increasing the risk of ischemia, or causing the subject to present one or more symptoms of ischemia and treating or Other exemplary examples of hereditary disorders, symptomatic conditions, traumatic disorders, chronic conditions, medical interventions, or other conditions suitable for remission include surgery, chemotherapy, radiation therapy, or cells , Ischemia due to tissue or organ transplant or graft.

  In various embodiments, the method of the invention comprises cerebrovascular ischemia, myocardial ischemia, ischemic limb (CLI), myocardial ischemia (especially chronic myocardial ischemia), ischemic cardiomyopathy, cerebrovascular ischemia, renal ischemia. It is suitable for treating pulmonary ischemia, intestinal ischemia, and the like.

  In various embodiments, the invention provides for ischemic tissue, wherein it is desirable that the therapeutic cell compositions disclosed herein increase blood flow, oxygen supply, glucose supply, or nutrient supply to the tissue. It is contemplated that it can be used to treat.

  In some embodiments, the 15-PGDH inhibitor is a preparation of stem cells that can generate tissue stem cells, eg, neural stem cells, mesenchymal stem cells, or other tissues, and / or preparation of pluripotent stem cells. Can be administered.

  In one embodiment, tissue stem cells can be obtained from pluripotent stem cell sources, such as induced pluripotent stem cells (iPSC) and embryonic stem cells (ESC). As used herein, the term “induced pluripotent stem cell” or “iPSC” refers to a non-pluripotent cell that has been reprogrammed to a pluripotent state. As soon as the subject's cells are reprogrammed to a pluripotent state, the cells can be programmed into the desired cell type, eg, hematopoietic stem or progenitor cells. As used herein, the term “reprogramming” refers to a method of increasing the potency of a cell to a more undifferentiated state. As used herein, the term “programming” refers to a method of decreasing the potency of a cell or causing a cell to differentiate into a more differentiated state.

  In some embodiments, tissue stem cells and / or pluripotent stem cells can be administered or contacted with one or more 15-PGDH inhibitors described herein ex vivo. And a therapeutic composition is provided. In one embodiment, the therapeutic composition can comprise a population of tissue stem cells treated with one or more 15-PGDH inhibitors ex vivo.

  In certain embodiments, the therapeutic composition comprises a population of cells, wherein the population of cells is about 95% to about 100% tissue stem cells. The invention may improve the efficiency of stem cell therapy using, in part, a therapeutic composition of highly purified tissue stem cells, eg, a composition comprising a population of cells, wherein the cells comprise about 95% tissue stem cells. Contemplate.

  In some embodiments, the therapeutic composition comprises a population of cells, wherein the population of cells is about 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15% , 20%, 25%, or less than 30% tissue stem cells. The population of cells, in some embodiments, is less than about 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 25%, or 30% tissue Contains stem cells. In other embodiments, the population of cells is about 0.1% to about 1%, about 1% to about 3%, about 3% to about 5%, about 10% -15%, about 15% -20%, About 20% -25%, about 25% -30%, about 30% -35%, about 35% -40%, about 40% -45%, about 45% -50%, about 60% -70%, about 70% -80%, about 80% -90%, about 90% -95%, or about 95% to about 100% tissue stem cells.

  The tissue stem cells in the therapeutic composition of the present invention may be autologous / self-sourced (“self”) or non-autologous (“nonself”, eg, allogeneic, syngeneic or xenogeneic) to the subject to which the therapeutic composition is administered. ). “Autologous” as used herein refers to cells from the same subject. “Homologous” refers herein to cells of the same species that are genetically different from the comparative cells. “Syngeneic” as used herein refers to cells of a different subject that are genetically identical to a comparative cell. “Heterologous” as used herein refers to a cell of a different species than the comparative cell.

  Preparations of tissue stem cells administered with one or more 15-PGDH inhibitors and / or therapeutic compositions comprising tissue stem cells and one or more 15-PGDH inhibitors are damaged in order to improve tissue stem cell transplantation. Used in the treatment of damaged tissue and to further reduce tissue damaged tissue and / or enhance repair to tissue damaged by stem cell mobilization and / or increase cell survival at the site of tissue damage Can do.

  Symptomatic conditions, traumatic disorders, chronic medical conditions, medical interventions that cause or are associated with the need for tissue damage and repair, and are therefore suitable for treatment or remission using the methods described herein , Or other medical conditions include, but are not limited to: acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusion, arteries Sclerosis, articular cartilage defect, aseptic systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, fracture, fracture, cerebral edema, cerebral hypoperfusion, Buerger's disease, burns, cancer, cardiovascular disease, Cartilage injury, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic infection, chronic mesenteric ischemia, lameness, congestive heart failure, connective tissue injury, contusion, coronary artery Disease (CAD), severe ischemic limb (CLI), Crohn's disease, deep vein thrombosis, deep wound, delayed ulcer healing, delayed wound healing, diabetes (type I and type II), diabetes, diabetic neuropathy, diabetes Induced ischemia, disseminated intravascular coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, frostbite, hereditary hemorrhagic telangiectatic ischemic vascular disease, hyperoxia injury, hypoxia, Inflammation, inflammatory bowel disease, inflammatory disease, injured tendon, intermittent claudication, intestinal ischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic kidney disease, imaginary Blood vascular disease, ischemic-reperfusion injury, laceration, left main coronary artery lesion, ischemic limb, lower limb ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease Peripheral arterial disease (PAD), peripheral arterial disease, peripheral ischemia, peripheral Neuropathy, peripheral vascular disease, precancer, pulmonary edema, pulmonary embolism, remodeling disorder, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcer, solid organ transplantation, spinal cord injury, stroke, subchondral bone cyst, Thrombosis, thrombotic cerebral ischemia, tissue ischemia, transient cerebral ischemic attack (TIA), traumatic brain injury, ulcerative colitis, renal vascular disease, vascular inflammatory condition, von Hippel-Lindau syndrome, and A wound to a tissue or organ.

  Genetic disorders, symptomatic conditions, traumatic disorders, chronic medical conditions, medical conditions that cause or are associated with the need for tissue damage and repair, suitable for treatment or remission using the methods of the invention Other illustrative examples of interventions or other medical conditions include surgery, chemotherapy, radiation therapy, or ischemia due to cell, tissue, or organ transplant or graft.

  In various embodiments, the method of the invention comprises cerebrovascular ischemia, myocardial ischemia, ischemic limb (CLI), myocardial ischemia (especially chronic myocardial ischemia), ischemic cardiomyopathy, cerebrovascular ischemia, renal ischemia. It is suitable for treating pulmonary ischemia, intestinal ischemia, and the like.

  In other embodiments, the 15-PGDH inhibitor can be administered to a bone marrow transplant donor or hematopoietic stem cell donor to increase the fitness of the donor bone marrow graft or donor hematopoietic stem cell graft.

  In other embodiments, the 15-PGDH inhibitor can also be administered to the bone marrow of a subject to increase stem cells in the subject or to increase the fitness of the bone marrow as a donor graft. .

  In still other embodiments, the 15-PGDH inhibitor enhances hematopoietic stem cell graft or umbilical cord blood stem cell graft survival to alleviate bone marrow graft rejection, enhance bone marrow graft survival In order to increase the engraftment of hematopoietic stem cell grafts or umbilical cord stem cell grafts and / or to reduce the number of units of cord blood required for transplantation into a subject be able to. Administration can be, for example, after treatment of a subject or subject's bone marrow with radiation therapy, chemotherapy, or immunosuppressive therapy.

  In other embodiments, the 15-PGDH inhibitor can be administered to recipients of bone marrow transplant, hematopoietic stem cell transplant, or cord blood stem cell transplant to reduce administration of other treatments or growth factors.

  In some embodiments, the 15-PGDH inhibitor is derived from a disease after bone marrow transplant, after cord blood transplant, after hematopoietic stem cell transplant, after conventional chemotherapy, after radiation therapy, and including, but not limited to: In individuals with multiple neutropenia, can be administered to subjects to enhance neutrophil recovery: aplastic anemia, myelodysplasia, myelofibrosis, from other bone marrow diseases Post-infection with viruses, including but not limited to HIV, CMV, and parvovirus, and neutropenia, drug-induced neutropenia, immune neutropenia, idiopathic neutropenia .

  In other embodiments, the 15-PGDH inhibitor is derived from a disease after bone marrow transplant, after cord blood transplant, after hematopoietic stem cell transplant, after conventional chemotherapy, after radiation treatment, and including, but not limited to: In individuals with neutropenia, can be administered to subjects to enhance platelet recovery: aplastic anemia, myelodysplasia, myelofibrosis, thrombocytopenia from other bone marrow diseases After infection with viruses, including but not limited to HIV, CMV, and parvovirus, and drug-induced thrombocytopenia, immune thrombocytopenia, idiopathic thrombocytopenic purpura, idiopathic thrombocytopenia.

  In still other embodiments, the 15-PGDH inhibitor is from a disease after bone marrow transplant, after cord blood transplant, after hematopoietic stem cell transplant, after conventional chemotherapy, after radiation therapy, and including but not limited to: Can be administered to a subject to enhance hemoglobin recovery in individuals with multiple anemias: aplastic anemia, myelodysplasia, myelofibrosis, anemia from other bone marrow diseases, drug anemia After infection by viruses, including but not limited to, immune-mediated anemia, chronic disease anemia, idiopathic anemia, and HIV, CMV, and parvovirus.

  In some embodiments, the 15-PGDH inhibitor may be administered after bone marrow transplantation, after cord blood transplantation, after hematopoietic stem cell transplantation, after conventional chemotherapy, after radiation treatment, in individuals with other bone marrow diseases after viral infection. Can be administered to a subject to increase the number of bone marrow stem cells in individuals with and with cytopenias.

  In other embodiments, the 15-PGDH inhibitor is a cytokine administered to an individual with cytopenias, including but not limited to neutropenia, thrombocytopenia, lymphopenia, and anemia. Can be administered to a subject to enhance the response to. Cytokines whose responses can be enhanced by SW033291 include, but are not limited to: G-CSF, GM-CSF, EPO, IL-3, IL-6, TPO, SCF, and TPO-RA (thrombopoietin) Receptor agonists).

  In a further embodiment, the 15-PGDH inhibitor mitigates graft rejection, enhances graft survival, after treatment of a subject or subject's bone marrow with radiation therapy, chemotherapy, or immunosuppressive therapy Toxic effects of cytoxan, fludarabine, toxic effects of chemotherapy, or toxic effects of immunosuppressive therapies to confer resistance to toxicity or lethal effects of radiation exposure to enhance graft survival Can be administered to a subject or a subject's tissue graft to confer resistance to, reduce infection, and / or reduce radiation-induced lung toxicity.

  In other embodiments, the 15-PGDH inhibitor is used in a tissue stem cell transplant, such as, but not limited to, a recipient of a stem cell transplant for hematopoietic stem cells, neural stem cells, mesenchymal stem cells, or other tissues, It can be administered to accelerate tissue regeneration and repair after transplantation.

  In some embodiments, administration of a 15-PGDH inhibitor can be combined with G-CSF for the purpose of increasing neutrophils.

  In other embodiments, administration of a 15-PGDH inhibitor can be combined with hematopoietic cytokines for the purpose of increasing neutrophils.

  In yet other embodiments, administration of a 15-PGDH inhibitor can be combined with G-CSF for the purpose of increasing and / or mobilizing peripheral blood hematopoietic stem cells.

  In other embodiments, administration of a 15-PGDH inhibitor can be combined with hematopoietic cytokines for the purpose of increasing and / or mobilizing peripheral blood hematopoietic stem cells.

  In some embodiments, administration of a 15-PGDH inhibitor can be combined with a second agent, eg, prixafor, for the purpose of increasing and / or mobilizing peripheral blood hematopoietic stem cells. .

  In other embodiments, administration of a 15-PGDH inhibitor is combined with G-CSF for the purpose of increasing and / or mobilizing peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation. be able to.

  In yet other embodiments, administration of a 15-PGDH inhibitor is combined with hematopoietic cytokines for the purpose of increasing and / or mobilizing peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation. be able to.

  In other embodiments, administration of a 15-PGDH inhibitor increases the number of peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation and / or for the purpose of mobilizing the second agent, For example, it can be combined with prerixaphor.

  In yet other embodiments, administration of a 15-PGDH inhibitor can be combined with G-CSF for the purpose of increasing the number of hematopoietic stem cells in the blood or bone marrow.

  In other embodiments, administration of a 15-PGDH inhibitor can be combined with hematopoietic cytokines for the purpose of increasing the number of hematopoietic stem cells in the blood or bone marrow.

  In other embodiments, the 15-PGDH inhibitor treats and / or prevents fibrosis and various fibrotic diseases, disorders or conditions, and fibrotic conditions such as collagen deposition, inflammatory cytokine expression, and inflammatory cells. Can be used to reduce infiltration.

  In some embodiments, the method of treating or preventing a fibrotic disease, disorder or condition has a strength, at least one symptom or characteristic of the fibrotic disease, disorder or condition, or other related disease, disorder or condition, Administration of a therapeutically effective amount of a 15-PGDH inhibitor to a subject in need thereof, such that the severity or frequency is reduced or onset is delayed.

  As used herein, the term “fibrotic” disease, disorder, or condition, in whole or in part, causes overproduction of fibrous material, eg, overproduction of fibrotic material within the extracellular matrix, or normal. Includes diseases, disorders, or conditions characterized by replacement by abnormal, non-functional, and / or excessive accumulation of matrix-related components of tissue elements. A fibrotic disease, disorder, or condition can include acute and chronic, clinical or asymptomatic symptoms, in which case a fibrogenic associated biological pathology is evident.

  Examples of fibrotic diseases, disorders and conditions include the following: systemic sclerosis, multifocal fibrosis, renal systemic fibrosis, scleroderma (morphea, multiple morphea, or strong linear) Scleroderma), scleroderma graft-versus-host disease, renal fibrosis (including glomerulosclerosis, renal tubulointerstitial fibrosis, progressive renal disease or diabetic nephropathy), cardiac fibrosis ( For example, myocardial fibrosis), pulmonary fibrosis (eg, glomerulosclerosis pulmonary fibrosis, idiopathic pulmonary fibrosis, silicosis, asbestosis, interstitial lung disease, interstitial fibrotic lung disease, And chemotherapy / radiation-induced pulmonary fibrosis), oral fibrosis, endocardial myocardial fibrosis, deltoid fibrosis, pancreatitis, inflammatory bowel disease, Crohn's disease, nodular fasciitis, eosinophils Fasciitis, various degrees of normal muscle tissue Nerve in general fibrosis syndrome, retroperitoneal fibrosis, liver fibrosis, cirrhosis, chronic renal failure; myelofibrosis (bone marrow-fibrosis), drug-induced ergot poisoning, Li Fraumeni syndrome Glioblastoma, sporadic glioblastoma, myeloid leukemia, acute myeloid leukemia, myelodysplastic syndrome, myeloproliferative syndrome, gynecological cancer, Kaposi's sarcoma, leprosy, collagen colon Inflammation, acute fibrosis, organ-specific fibrosis, etc.

  Exemplary organ-specific fibrosis disorders include pulmonary fibrosis, pulmonary hypertension, cystic fibrosis, asthma, chronic obstructive pulmonary disease, liver fibrosis, renal fibrosis, NASH, etc. It is not limited. Many fibrotic diseases, disorders or conditions have extracellular matrix disorder and / or exaggerated deposition in the affected tissue. Fibrosis is associated with inflammation, occurs as a symptom of the underlying disease, and / or can be caused by a surgical procedure or wound healing process. Unexamined fibrosis can result in destruction of the underlying organ or tissue structure and is commonly referred to as scarring.

  In some embodiments, 15-PGDH inhibitors can be used to treat or prevent pulmonary fibrosis. Pulmonary fibrosis is pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, sarcoidosis, cystic fibrosis, familial pulmonary fibrosis, silicosis, asbestosis, coal mining Pneumoconiosis, carbon pneumoconiosis, hypersensitivity pneumonia, pulmonary fibrosis caused by inhalation of inorganic dust, pulmonary fibrosis caused by infectious pathogens, pulmonary fibrosis caused by inhalation of harmful gases, aerosols, chemical dust, fume or vapor , Drug-induced interstitial lung disease, or pulmonary hypertension, and combinations thereof.

  Pulmonary fibrosis is characterized by fibroblast proliferation, excessive accumulation of extracellular matrix proteins, and progressive scars of lung tissue with abnormal alveolar structures. Thickened and hard tissue can make it difficult for the lungs to work properly, can lead to respiratory problems such as shortness of breath, and can ultimately be fatal. Pulmonary fibrosis can be caused by acute lung injury, viral infection, exposure to toxins, radiation, chronic disease, drug therapy, or can be idiopathic (ie, the underlying cause has not been found).

  Classical findings in idiopathic pulmonary fibrosis show diffuse peripheral scars of the lung with small bubbles (known as intraalveolar cysts), often adjacent to the outer membrane of the lung surface, often at the bottom of the lung . Idiopathic pulmonary fibrosis often has a slow and unrelenting progression. Early on, patients often complain of unexplained dry cough. Second, caused by progressively less activity, shortness of breath (dyspnea) begins and worsens over time. Eventually, shortness of breath can be disabling, restricting all activities and even happening when sitting still. Very rarely, fibrosis can become rapidly progressive, with dyspnea and disability occurring weeks to months after the onset of the disease. This form of pulmonary fibrosis is called Hanman-Rich syndrome.

  Pulmonary hypertension is characterized by increased blood pressure in the pulmonary vasculature, including pulmonary arteries, pulmonary veins, and / or pulmonary capillaries. An abnormally high pressure pulls the right ventricle of the heart and enlarges it. Over time, the right ventricle becomes less capable of losing enough blood into the lungs and can lose, leading to the development of heart failure. Pulmonary hypertension can occur as a result of other medical conditions such as: chronic liver disease and cirrhosis; rheumatic disorders such as scleroderma or systemic lupus erythematosus (Lupus); and tumors, emphysema, chronic obstructive pulmonary disease (COPD) and lung pathologies including pulmonary fibrosis. Pulmonary fibrosis can lead to narrowing of the pulmonary vasculature, resulting in pulmonary hypertension.

  Chronic obstructive pulmonary disease (COPD) is a common pulmonary disease often associated with chronic bronchitis or emphysema. Symptoms often include coughing, mucus accumulation, fatigue, wheezing, and respiratory infections.

  Chronic bronchitis and emphysema are lung diseases with narrowed airways. This limits the flow of air to and from the lungs and causes shortness of breath (dyspnea). In clinical practice, COPD is defined by its inherently low airflow in pulmonary function tests.

  Chronic bronchitis results from lung damage and inflammation in the large airways. In the lung airways, the hallmarks of chronic bronchitis are increased numbers of airway goblet cells and mucous glands (hyperplasia) and increased size (hypertrophy). As a result, more mucus is present in the airway than usual, contributing to narrowing of the airway and causing a cough with phlegm. Microscopically, there is infiltration by inflammatory cells in the airway wall. Inflammation is followed by scarring and remodeling, thickening of the walls, which also causes airway narrowing. As chronic bronchitis progresses, squamous metaplasia (abnormal changes in the tissue lining inside the airways) and fibrosis (further airway wall thickening and scarring) occur. The result of these changes is airflow limitation and difficult breathing.

  Asthma is a chronic lung disease characterized by airway inflammation and stenosis. Asthma causes periods of recurrence of wheezing, chest tightness, shortness of breath, and cough. Mucus swelling and overproduction can cause further airway narrowing and worsening of symptoms. There is evidence that increased matrix degradation can occur in asthma, which can contribute to organic changes in the airways in asthma (Roberts et al (1995) Chest 107: 111 S-117S, which is hereby incorporated by reference in its entirety. Incorporated in the description). Treatment of extracellular matrix degradation can ameliorate the symptoms of asthma.

  Cystic fibrosis is a recessive multisystem hereditary disease characterized by abnormal transport across the epithelium of chloride and sodium, causing dense, viscous secretions in the lungs, pancreas, liver, intestine and reproductive system . Cystic fibrosis is caused by a mutation in the gene for the protein cystic fibrosis membrane conductance regulator (CFTR). Lung disease results from airway clogging due to mucus accumulation, decreased mucociliary clearance, and resulting inflammation, which can cause fibrotic damage and structural changes to the lungs. Fibrotic lung damage progresses over time and some patients with cystic fibrosis require lung transplantation.

  Common symptoms in subjects with cystic fibrosis include, but are not limited to: accumulation of sticky mucus, production of large amounts of sputum, frequent chest infections, frequent cough, frequent Shortness of breath, inflammation, motor disability, opportunistic infection of the lungs and sinus (eg, but not limited to Staphylococcus aureus, Haemophilus influenzae, Mycobacterium abium, and Pseudomonas aeruginosa), pneumonia, tuberculosis, bronchi Dilatation, hemoptysis, pulmonary hypertension (and resulting heart failure), hypoxia, respiratory failure, allergic bronchopulmonary aspergillosis, mucus in the sinuses, sinus infection, facial pain, fever, excessive rhinorrhea, nose Development of polyps, cardiopulmonary complications, CF-related diabetes, rectal prolapse, pancreatitis, malabsorption, bowel obstruction, exocrine pancreas, biliary obstruction, and cirrhosis.

  In other embodiments, 15-PGDH inhibitors can be used to treat or prevent a fibrotic disease, disorder or condition caused by post-surgical adhesion formation. Post-surgical adhesion formation is a common complication of surgery. Mechanical damage, ischemia, and formation of infection-derived adhesions can increase morbidity and mortality after surgery. With elaborate surgical procedures, the size of adhesion formation can be reduced, but adhesions are rarely removed and effective adjuvant therapy is required. Reducing the fibrosis associated with this process could reduce surgical pain, obstruction, and other complications, and promote healing and recovery.

  Wounds (ie, tears, openings) in mammalian tissue result in tissue destruction and microvasculature coagulation at the wound surface. Such tissue repair represents an ordered and controlled cellular response to injury. Soft tissue wounds heal similarly, regardless of size. Tissue growth and repair is a biological system in which cell proliferation and angiogenesis occur in the presence of an oxygen gradient. The continuous morphological and structural changes that occur during tissue repair are well characterized and sometimes quantified (see, for example, Hunt, TK, et al., “Coagulation and Macrophage simulation of angiogenesis and wound healing, "in The Surgical Wound, pp. 1-18, ed. F. Dineen & G. Hidrick-Smith (Lea & H.). Cell morphology consists of three distinct zones. The central avascular wound space is hypoxic, acidogenic and percarbonate, and has a high lactate level. Adjacent to the wound space is a gradient zone of local anemia (ischemia) that is assembled by dividing fibroblasts. Following the leading zone is an area of active collagen synthesis characterized by mature fibroblasts and many newly formed capillaries (ie, neovascularization). US Pat. Nos. 5,015,629 and 7,022,675, each incorporated herein by reference, disclose methods and compositions for increasing the rate of wound repair.

  In some embodiments, a 15-PGDH inhibitor can be used to reduce or prevent scar formation in a subject by administering it to a subject in need of treatment. Scar formation is a natural part of the healing process. Unregulated collagen synthesis and deposition in the wound can result in excessive, thick or raised scar formation. In general, the larger the wound, the longer it takes to heal and the greater the potential for problematic scars.

  In other embodiments, 15-PGDH inhibitors can be used to reduce or prevent scar formation or scleroderma on the skin. There are several types of scars on the skin. A hypertrophic scar is a raised, pinkish area located inside the border of the original injury. They are often described as ugly. In some cases, the hypertrophic scar contracts and disappears naturally. Keloids are raised, dark red areas that tend to cover much larger areas than the original damage. Even when surgically removed, keloids tend to recur. Atrophic scars are skin depressions, such as those that sometimes form from severe acne. They are caused by inflammation that destroys the collagen during the remodeling process, leaving an area of press fit.

  In some embodiments, 15-PGDH inhibitors can be used to treat or prevent systemic sclerosis. Systemic sclerosis is a systemic connective tissue disease characterized by microvascular changes, immune system disturbances, and massive deposition of collagen and other matrix substances in connective tissue. Systemic sclerosis is a clinically heterogeneous systemic disorder that affects the connective tissue of the skin and internal organs such as the gastrointestinal tract, lungs, heart, and kidneys. Reduction of fibrosis due to systemic sclerosis may ameliorate symptoms and / or prevent further complications in the affected tissue.

  In other embodiments, 15-PGDH inhibitors can be used to treat or prevent liver fibrosis. Liver fibrosis may result from: chronic liver disease, virus-induced cirrhosis, hepatitis B virus infection, hepatitis C virus infection, hepatitis D virus infection, schistosomiasis, primary biliary cirrhosis Alcoholic liver disease or non-alcoholic steatohepatitis (NASH), NASH-related cirrhosis obesity, diabetes, protein nutritional disorders, coronary artery disease, autoimmune hepatitis, cystic fibrosis, α1 antitrypsin deficiency, primary biliary Cirrhosis, drug reaction and exposure to toxins.

  Nonalcoholic steatohepatitis (NASH) is a common liver disease. This is similar to alcoholic liver disease but occurs in people who drink little or no alcohol. The main feature in NASH is fat in the liver, accompanied by inflammation and damage. Nevertheless, NASH can be severe and can lead to cirrhosis, in which case the liver is permanently damaged and scarred and can no longer work properly.

  NASH is usually an asymptomatic disease with few or no symptoms. Patients are generally well in the early stages and only begin to have symptoms—such as fatigue, weight loss, and weakness—when disease progresses more or cirrhosis develops. It takes several years or even decades for NASH to progress. The process may cease and in some cases may even spontaneously begin to reverse without specific therapy. Alternatively, NASH can become progressively worse, causing scars or fibrosis to appear and accumulate in the liver. As fibrosis worsens, cirrhosis develops, in which case the liver becomes markedly scarred and stiffened and cannot function normally. Not all individuals with NASH will develop cirrhosis, but once there is severe scar or cirrhosis, few treatments can stop progression. Persons with cirrhosis experience fluid retention, muscle wasting, intestinal bleeding, and liver failure. Liver transplantation is the only treatment for advanced cirrhosis with liver failure, and transplantation is increasingly practiced in people with NASH. NASH ranks next to hepatitis C and alcoholic liver disease as one of the main causes of cirrhosis in the United States.

  In some embodiments, 15-PGDH inhibitors can be used to treat or prevent renal fibrosis. Renal fibrosis can result from dialysis after renal failure, catheterization, nephropathy, glomerulosclerosis, glomerulonephritis, chronic renal dysfunction, acute kidney injury, end-stage renal disease or renal failure.

  Renal (renal) fibrosis results from excessive formation of fibrous connective tissue in the kidney. Renal fibrosis causes significant morbidity and mortality, requiring dialysis or kidney transplantation. Fibrosis can occur in either nephrons, filtration of the renal functional unit, or resorbable components. Many factors can contribute to the disruption of physiology involved in renal scarring, particularly the self-regulation of glomerular filtration. This in turn leads to replacement with an extracellular matrix in which normal structures are accumulated. Various changes in individual cell physiology lead to the production of many peptides and non-peptide fibrogens that stimulate changes in the balance between extracellular matrix synthesis and degradation in favor of scarring.

  In some embodiments, the symptoms of tissue organ fibrosis may include inflammation. In these embodiments, a therapeutically effective amount of a 15-PGDH inhibitor administered to a subject in need thereof can be an amount effective to reduce or reduce the number of inflammatory cells in a tissue or organ. . In order to determine a reduction or reduction in the number of inflammatory cells, a relevant sample can be obtained from the subject. In a non-limiting embodiment, beneficial effects can be assessed by demonstrating a reduction in neutrophil count in BAL fluid from subjects with cystic fibrosis. The over-mobilization of neutrophils into the respiratory tract of patients with CF is an important predictor of lung disease severity in CF and thus an important therapeutic target. Methods for measuring such cell numbers are well known in the art and include, but are not limited to, FACS technology. In some embodiments, the method can include reducing the number of neutrophils in the BAL fluid from the subject as compared to the control. Any suitable control, such as a cystic fibrosis subject not treated with a 15-PGDH inhibitor, can be used for comparison. In some embodiments, a reduction in the number of inflammatory cells, eg, neutrophils, provides the subject with clinical benefit. In various embodiments, the reduction in the number of inflammatory cells is at least 5%, 10%, 15%, 20%, 25%, 50% or more compared to the control.

  In another embodiment, the beneficial effect of a 15-PGDH inhibitor can be assessed by a reduction of one or more inflammatory biomarkers in a relevant sample from the subject. In various non-limiting embodiments, the inflammatory biomarker can comprise or consist of one or more of cytokines or inflammatory cytokines associated with fibrosis. Such cytokines include, for example, IL1β, MIP2 (eg, CCL3 or CCL4), IFNδ, TGFβ, TNFα, IL-6, MCP-1, IL2, and IL-10 in BAL fluid. Methods for measuring the amount of such biomarkers are well known in the art and include, but are not limited to, ELISA. Thus, in this embodiment, the method may further comprise reducing the amount of one or more inflammatory biomarkers in the sample from the subject as compared to the control.

  In other embodiments, a 15-PGDH inhibitor can be used in a method for reducing or reducing collagen secretion or deposition in a tissue or organ of a subject, such as lung, liver, skin or heart. The method can include administering a therapeutically effective amount of a 15-PGDH inhibitor to a subject in need thereof. The subject may have or be at risk for excessive collagen secretion or deposition in a tissue or organ, such as the kidney, lung, liver, intestine, colon, skin or heart. Usually, excessive collagen secretion or collagen deposition in organs results from injury or invasion. Such damage or invasion is organ specific. The 15-PGDH inhibitor can be administered for a period of time sufficient to completely or partially reduce or reduce the level of collagen deposition in a tissue or organ. A sufficient period of time can be one week to one month, or one to two months, or two months or more during a week. For chronic conditions, the 15-PGDH inhibitor can be conveniently administered during the lifetime.

  A 15-PGDH inhibitor used to treat a fibrotic disease, disorder or condition and / or reduce collagen deposition is applied to cells where the putative inhibitor compound expresses 15-PGDH, and then 15 -Can be identified using assays in which a functional effect on PGDH activity is determined. A sample or assay containing 15-PGDH, treated with a potential inhibitor, is compared to a control sample without inhibitor and the extent of effect is examined. Control samples (no treatment with modulator) are assigned a relative 15-PGDH activity value of 100%. Inhibition of 15-PGDH is achieved when the 15-PGDH activity value relative to the control is about 80%, optionally 50% or 25%, 10%, 5% or 1%.

In addition, the model organism, PGE ₂ signaling hepatotoxic agent, e.g., after exposure to acetaminophen, stimulate liver regeneration, increase survival. Thus, the 15-PGDH inhibitors described herein increase liver regeneration after liver resection in other situations, including after liver surgery, after living donor liver, or after undergoing liver transplantation. Or, can be used to increase liver regeneration and increase survival after exposure to hepatotoxic agents such as, but not limited to, acetaminophen and similar compounds.

  PGE1 analogs have also been used in the treatment of erectile dysfunction. Thus, in some embodiments, the 15-PGDH inhibitors described herein can be used alone or in combination with prostaglandins for the treatment of erectile dysfunction.

  It will be appreciated that other 15-PGDH inhibitors can be used in the methods described herein. These other 15-PGDH inhibitors can include known 15-PGDH inhibitors, including, for example: US Patent Application Publication No. 2006/0034786 and US Pat. No. 7,705,041 Described tetrazole compounds of formula (I) and (II), 2-alkylideneaminooxyacetamide compounds of formula (I), heterocyclic compounds of formulas (VI) and (VII), and pyrazole compounds of formula (III) A benzylidene-1,3-thiazolidine compound of formula (I), described in US Patent Application Publication No. 2007/0071699; phenylfurylmethylthiazolidine-2,4 described in US Patent Application Publication No. 2007/0078175; -Dione and phenylthienylmethylthiazolidine-2,4-dione compounds; US patents Thiazolidenedione derivatives described in Japanese Patent Application Publication No. 2011/0269954; phenylfuran, phenylthiophene, or phenylpyrazole compounds described in US Pat. No. 7,294,641; 5- (3,5-disubstituted Phenylazo) -2-hydroxybenzene-acetic acid and salts; and lactones described in US Pat. No. 4,725,676; azo compounds described in US Pat. No. 4,889,846; and PCT / US2014 / 15-PGHD inhibitors described in 060761 and US Patent Application Publication No. 2015 / 0072998A1, all of which are hereby incorporated by reference in their entirety.

  The 15-PGDH inhibitors described herein can be provided in a pharmaceutical or cosmetic composition depending on the condition or cosmetic condition or disorder being treated. A pharmaceutical composition comprising a 15-PGDH inhibitor as described herein as an active ingredient component comprises a derivative and a pharmaceutically acceptable carrier (s) or excipient (s) according to conventional methods. It can be prepared by mixing or diluting a 15-PGDH inhibitor with a diluent. The pharmaceutical composition can further include fillers, anti-aggregating agents, lubricants, wetting agents, flavoring agents, emulsifying agents, preservatives and the like. The pharmaceutical composition can be formulated into a suitable formulation according to methods known to those skilled in the art, so that it can be used for immediate release, controlled release or 15-PGDH inhibitor administration after administration to a mammal. Sustained release can be provided.

  In some embodiments, the pharmaceutical composition can be formulated into a parenteral or oral dosage form. Solid dosage forms for oral administration were obtained by adding excipients to the 15-PGDH inhibitor, optionally with binders, disintegrants, lubricants, colorants, and / or flavoring agents. It can be produced by molding the mixture into tablets, dragees, granules, powders or capsules. Additives that can be added to the composition may be conventional in the art. For example, examples of excipients include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicate, and the like. Exemplary binders include water, ethanol, propanol, sweet syrup, sucrose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphonate and polypyrrolidone. It is done. Examples of disintegrants include dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride and lactose. In addition, purified talc, stearate, sodium borate, and polyethylene glycol can be used as lubricants; and sucrose, orange peel, citric acid, tartaric acid can be used as flavoring agents. In some embodiments, pharmaceutical compositions can be made into aerosol formulations that are administered by inhalation (eg, they can be nebulized).

  The 15-PGDH inhibitors described herein can be combined with flavoring agents, buffers, stabilizers, etc., according to conventional methods, and incorporated into oral liquid dosage forms such as solutions, syrups or elixirs. Can do. One example of a buffer may be sodium citrate. Examples of stabilizers include tragacanth, gum arabic and gelatin.

  In some embodiments, the 15-PGDH inhibitors described herein are added to this by adding a pH adjuster, buffer, stabilizer, relaxant, local anesthetic, eg, subcutaneous, muscle It can be incorporated into injectable dosage forms for internal or intravenous routes. Examples of pH adjusters and buffers include sodium citrate, sodium acetate and sodium phosphate. Examples of stabilizers include sodium pyrosulfite, EDTA, thioglycolic acid and thiolactic acid. The local anesthetic may be procaine HCl, lidocaine HCl, or the like. The relaxing agent may be sodium chloride, glucose or the like.

  In other embodiments, the 15-PGDH inhibitors described herein are in accordance with conventional methods and pharmaceutically acceptable carriers known in the art, such as polyethylene glycol, lanolin, Cocoa butter or fatty acid triglycerides can be incorporated into suppositories, if desired, by addition with a surfactant such as Tween.

  The pharmaceutical compositions can be formulated into various dosage forms as described above and then administered through a variety of routes including oral, inhalation, transdermal, subcutaneous, intravenous or intramuscular routes. The dosage can be a pharmaceutically effective amount. A pharmaceutically effective amount can be the amount of a 15-PGDH inhibitor that treats or ameliorates alopecia, cardiovascular disease, gastrointestinal disease, wounds, and kidney disease. The pharmaceutically effective amount of the compound is appropriately determined by the type and severity of the disease being treated, the age, sex, weight and health status of the patient being treated, route of administration, duration of therapy, and the like. In general, an effective amount of the compound may range from about 1-1000 mg for oral administration, about 0.1-500 mg for intravenous administration, and about 5-1,000 mg for rectal administration. In general, the daily dosage for an adult is in the range of about 0.1 to 5,000 mg, preferably about ˜1,000 mg, but cannot be determined uniformly. This is because it depends on the age, sex, weight and health status of the patient being treated. The formulation can be administered in divided doses once daily or several times daily.

  Cosmetic compositions comprising 15-PGDH inhibitors exclusively or primarily clean them, impart fragrance to them, modify their appearance and / or correct body odor and / or protect them Or in contact with various superficial parts of the human body (epidermis, body hair and hair system, nails, lips and genitals), or teeth or buccal mucosa for the purpose of maintaining them in good condition Any intended substance or preparation can be included.

  The cosmetic composition may be water or a mixture of water and at least one solvent selected from water and hydrophilic organic solvents, lipophilic organic solvents, amphiphilic organic solvents, and mixtures thereof. May include any acceptable media.

  For topical application, the cosmetic composition has a liquid or semi-liquid consistency of an aqueous, alcoholic, aqueous-alcoholic or oily solution or suspension, or a lotion or serum type dispersion, or pasty Incorporation into a ready-to-use or physiologically acceptable medium of an emulsion or multiple emulsion obtained by dispersion (O / W) of the fatty phase in the aqueous phase or vice versa (W / O) Can be administered in the form of free or dense powders, or else in the form of vesicle dispersions of microcapsules or microparticles, or of ionic and / or nonionic types. Thus, in the form of a salve, tincture, milk, cream, ointment, powder, patch, impregnated pad, solution, emulsion or vesicle dispersion, lotion, aqueous or anhydrous gel, spray, suspension, shampoo, aerosol or foam There may be. This may be anhydrous or aqueous. This may also include a solid preparation that constitutes a soap or cleansing cake.

  Cosmetic compositions may include hair care compositions, and in particular shampoos, set lotions, treatment lotions, styling creams or gels, reconstituted lotions for hair, masks, and the like. The cosmetic composition can be a cream, hair lotion, shampoo or conditioner. They can be used in particular in treatments with applications that may or may not be followed by rinsing or in the form of shampoos. Compositions comprising a propellant under pressure, in the form of a foam or in the form of a spray or aerosol, are also contemplated. Thus, this can be in the form of a lotion, serum, milk, cream, gel, salve, ointment, powder, balm, patch, impregnated pad, cake or foam.

  In particular, the composition for application to the scalp or hair is for example daily application of a hair care lotion for daily or twice weekly application, in particular of a shampoo or hair conditioner for twice weekly or weekly application. May be in the form of a liquid or solid soap for cleansing the scalp, of a hairstyle product (lacquer, hair set product or styling gel), of a treatment mask, or of a forming gel or cream for cleansing the hair it can. They can also be in the form of hair dyes or mascaras applied using brushes or combs.

  Moreover, for topical application to the eyelashes or body hair, the composition may be in the form of a colored or uncolored mascara that is applied to the eyelashes with a brush or to the mustache or mustache. For administration of a composition by injection, the composition may be in the form of an aqueous lotion or oily suspension. For oral use, the composition may be in the form of capsules, granules, oral syrups or tablets. According to a particular embodiment, the composition is in the form of a hair cream or hair lotion, shampoo, hair conditioner or mascara for the hair or eyelashes.

  In a known manner, the cosmetic composition also contains adjuvants that are common in the cosmetic field, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic additives, preservatives, antioxidants, solvents, fragrances, fillers, It may contain UV blockers, odor absorbers and pigments. The amounts of these various adjuvants are those conventionally used in the cosmetic field, for example from 0.1% to 20%, in particular not more than 10% of the total weight of the composition. According to their nature, these adjuvants can be introduced into the fatty phase, into the aqueous phase and / or into lipid globules.

  In some embodiments, the 15-PGDH inhibitor can be administered in combinatorial therapy or combination therapy comprising administration of the 15-PGDH inhibitor with one or more additional active agents. The phrase “combinatorial therapy” or “combination therapy” refers to 15-PGDH inhibitors as part of a particular treatment regimen intended to provide beneficial effects from the interaction of these therapeutic agents, and 1 Includes administration of one or more therapeutic agents. Administration of these therapeutic agents in combination is typically performed over a defined period of time (usually minutes, hours, days or weeks, depending on the combination selected). “Combinatorial therapy” or “combination therapy” refers to the administration of these therapeutic agents in a sequential manner (ie, where each therapeutic agent is administered at a different time), as well as those in a substantially simultaneous manner. Or the administration of at least two therapeutic agents. Substantial co-administration can be achieved, for example, by administering individual doses with a fixed ratio of each therapeutic agent, or multiple doses, to individual subjects for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be performed by any suitable route, including, but not limited to, the oral route, intravenous route, intramuscular route, and direct absorption via mucosal tissue. The therapeutic agents can be administered by the same route or by different routes. The order in which therapeutic agents are administered is not critical in the narrow sense.

  In some embodiments, the additional active agent is in particular a lipoxygenase inhibitor as described in EP 648488, in particular a bradykinin inhibitor as described in EP 845700, prostaglandins and their derivatives, in particular WO 98/33497, Those described in WO 95/11003, JP 97-10091, JP 96-134242, agonists or antagonists of receptors for prostaglandins, and EP 11755891 and EP 1175890, WO 01/74307, WO 01/74313, It can be selected from the non-prostanoic analogs of prostaglandins described in WO01 / 74314, WO01 / 74315 or WO01 / 72268.

  In other embodiments, the 15-PGDH inhibitor is an active agent such as a vasodilator, prostanoid agonist, antiandrogen, cyclosporine and their analogs, antibacterials, triterpenes, alone or in combination. Can be administered. Vasodilators can include potassium channel agonists, minoxidil and its derivatives, aminexil and US Pat. Nos. 3,382,247, 5,756,092, 5,772,990, 5,760,043. 5,466,694, 5,438,058, 4,973,474, chromakalin and diazoxide. As an antiandrogen, 5. α. -Reductase inhibitors such as finasteride and the compounds described in US Pat. No. 5,516,779, cyprosterone acetate, azelaic acid, its salts and derivatives thereof, and US Pat. No. 5,480,913 And the compounds described in US Pat. Nos. 5,411,981, 5,565,467 and 4,910,226. Antibacterial compounds include selenium derivatives, ketoconazole, triclocarban, triclosan, zinc pyrithione, itraconazole, pyridine acid, hinokitiol, mipyrosin, and compounds described in EP 680745, clinicine hydrochloride, benzoyl peroxide or benzyl and minocycline. Can be mentioned. Anti-inflammatory agents include inhibitors specific for Cox-2, such as NS-398 and DuP-697 (B. Batistini et al., DN & P 1994; 7 (8): 501-511) and / or as examples. Inhibitors of lipoxygenase, especially 5-lipoxygenase, such as zileuton (FJ Alvarez & RT Slade, Pharmaceutical Res. 1992; 9 (11): 1465-1473) are mentioned as examples.

  Other active compounds that can be present in pharmaceutical and / or cosmetic compositions include: aminexyl and its derivatives, 60-[(9Z, 12Z) octadec-9,12-dienoyl] hexapyranose, Benzalkonium chloride, benzethonium chloride, phenol, estradiol, chlorpheniramine maleate, chlorophyllin derivative, cholesterol, cysteine, methionine, benzyl nicotinate, menthol, peppermint oil, calcium pantothenate, panthenol, resorcinol, protein kinase C inhibitor , Prostaglandin H synthase 1 or COX-1 activator, or COX-2 activator, glycosidase inhibitor, glycosaminoglycanase inhibitor, pyroglutamate, hexasaccharide acid Or acyl hexasaccharide acids, substituted ethylene aryl, N-acylated amino acids, flavonoids, derivatives and analogs of ascomycin, histamine antagonists, triterpenes such as ursolic acid and US Pat. No. 5,529,769. , Compounds described in US Pat. No. 5,468,888, US Pat. No. 5,631,282, saponins, proteoglycanase inhibitors, agonists and antagonists of estrogen, pseudopterin, cytokines and growth Factor promoters, IL-1 or IL-6 inhibitors, IL-10 promoters, TNF inhibitors, vitamins such as vitamin D, vitamin B12 and pantothe Analogues Lumpur (panthotenol), hydroxy acids, benzophenones, esters of fatty acids, and hydantoins.

A pharmaceutical and / or cosmetic composition comprising a 15-PGDH inhibitor as described herein may additionally comprise at least one compound selected from, for example: prostaglandins, in particular prostaglandins Gin PGE ₁ , PGE ₂ , salts thereof, esters thereof, analogs thereof and derivatives thereof, particularly those described in WO 98/33497, WO 95/11003, JP 97-100091, JP 96-134242, Especially prostaglandin receptor agonists. This is particularly the case for at least one compound, for example an agonist of the prostaglandin F ₂ α receptor (acid form or precursor form, in particular ester form), for example latanoprost, fluprostenol, cloprostenol, bimatoprost, Unoprostone, an agonist of prostaglandin E ₂ receptor (and their precursors, especially esters, such as travoprost), such as 17-phenyl PGE ₂ , biprostol, butaprost, misoprostol, sulprostone, 16,16-dimethyl PGE ₂ , 11-deoxy PGE ₁ , 1-deoxy PGE ₁ , agonists of prostacyclin (IP) receptors and their precursors, in particular esters such as cicaprost, iloprost, isocarbacycline, beraprost, e Po Pros tenor, Treprostinil, agonists and their precursors of prostaglandin _{D 2} receptors, in particular esters, for example BW245C ((4S) - (3 - [(3R, S) -3- cyclohexyl-3-isopropyl - 2,5-dioxo) -4-imidazolidineheptanoic acid), BW246C ((4R)-(3-[(3R, S) -3-cyclohexyl-3-isopropyl] -2,5-dioxo) -4-imidazo Lysine heptanoic acid), agonists of receptors for thromboxane A2 (TP) and their precursors, in particular esters such as I-BOP ([1S- [1a, 2a (Z), 3b (1E, 3S), 4a]]-7- [3- [3-Hydroxy-4- [4- (iodophenoxy) -1-butenyl] -7-oxabicyclo- [2.2.1 ] Hept-2-yl] -5-heptenoic acid).

Conveniently, the composition comprises at least one 15-PGDH inhibitor as defined above and at least one prostaglandin or one prostaglandin derivative, such as, for example, a series 2 prostaglandin, such as In particular, saline or precursor forms, in particular PGF _2α and PGE _{2 of} esters (eg isopropyl esters), derivatives thereof such as 16,16-dimethyl PGE ₂ , 17-phenyl PGE ₂ and 16,16- Dimethyl PGF _2α , 17-phenyl PGF _2α , series 1 prostaglandins such as 11-deoxyprostaglandin E1, saline or ester forms of 1-deoxyprostaglandin E1, analogs thereof, in particular latanoprost, travo Prost, Full Pros Tenor, unoprostone, bimatoprost, cloprostenol, biprostol, butaprost, misoprostol, salts thereof or esters thereof may be included.

  The invention is further illustrated by the following examples. The examples are not intended to limit the scope of the claims.

Example 1
Analysis of Analogues of Lead Compound SW033291, 15-PGDH Inhibitor This example provides data on a group of structural analogs of SW033291. The data provided is the IC ₅₀ for each compound for inhibiting the enzymatic activity of recombinant 15-PGDH in an in vitro assay. Recombinant 15-PGDH is human unless otherwise specified. In addition, the examples provide water solubility data for selected analogs in pH 7 or pH 4 citrate buffer solutions.

  We first observed that the 15-PGDH inhibitory activity of all analogs tested to date, including SW033291, SW209415, SW208436, SW221345, SW211189 and SW221364, is due to the activity of the (+) optical isomer of these compounds. Indicates at least 98%. In SW033291 and SW209415, the (+)-isomer is the (R) enantiomer, while the absolute configuration of (+)-SW208436, SW212345, SW211689 and SW212364 has not yet been established.

ＳＷ２０９４１５の合成：代表的な手順

Example 2
The following examples describe the synthesis of SW209415 and its analogs and the resolution of racemic sulfoxide of SW209415 and its analogs on HPLC.

Synthesis of SW209415: typical procedure

SW209415.2- (Butylsulfinyl) -4- (1,2-dimethyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-3-amine. 2-(((Butylsulfinyl) methyl) thio) -4- (1,2-dimethyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile (0.14 mmol, 60 mg) To a solution of DMF (600 μl) / MeOH (300 μl) containing KOH (0.084 mmol, 4.70 mg, 0.6 eq, 2.0 M aqueous solution) was added. The reaction mixture was stirred at 32 ° C. for 10 minutes. Upon completion, the reaction was diluted with EtOAc, acidified with 5% aqueous AcOH to pH 7, the organic phase was separated, the aqueous layer was extracted twice with EtOAc, dried over magnesium sulfate, filtered, Concentrated under reduced pressure. The crude product was purified by flash chromatography to give the planned product in 97% isolated yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (s, 1H), 7.90 (d, J = 3.1 Hz, 1H), 7.50 (d, J = 3.2 Hz, 1H), 7. 11 (s, 1H), 4.76 (s, 2H), 3.39 (s, 3H), 3.27 (ddd, J = 12.9, 8.7, 6.4 Hz, 1H), 3. 09 (ddd, J = 12.8, 8.8, 6.9 Hz, 1H), 2.47 (s, 3H), 1.83 to 1.62 (m, 2H), 1.57 to 1.38 (M, 2H), 0.93 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 432.1 [M + H] ^< +>. The two enantiomers of SW209415 can be separated by chiral HPLC: Chiralpak AD-H, 10 × 250 mm, 5 μM, 100% MeOH.

  (−)-SW209415 · HCl. A solution of HCl in dioxane (30 μL of 4M) was added to a solution of (−)-SW209415 (50 mg, 0.12 mmol) in THF (1 mL). A yellow solid immediately precipitated and was collected after removal of the solvent.

(-)-SW209415.OTs. p-Toluenesulfonic acid monohydrate (22 mg, 0.12 mmol) was added to a solution of (−)-SW209415 (50 mg, 0.12 mmol) in THF (2 mL). A yellow solid immediately precipitated and was collected after removal of the solvent. Single crystals suitable for X-ray diffraction were obtained by gradual evaporation of the solution in acetone and the (−)-enantiomer proved to have S stereochemistry at sulfur.

2-(((Butylsulfinyl) methyl) thio) -4- (1,2-dimethyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile. 2-(((Butylthio) methyl) thio) -4- (1,2-dimethyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile (85 mg, 0.205 mmol). To a solution of containing CHCl _{3 /} AcOH (1: 1, 0.15 M) was added H ₂ O ₂ (0.31 mmol, 1.5 eq, 30% aqueous solution). The reaction mixture was stirred at 32 ° C. for 40 minutes. Upon completion, the reaction was diluted with EtOAc, washed with saturated NaHCO ₃ solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the planned product in 92% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (d, J = 3.1 Hz, 1H), 7.94 (s, 1H), 7.60 (d, J = 3.1 Hz, 1H), 7. 43 (s, 1H), 4.72 (d, J = 13.1 Hz, 1H), 4.41 (d, J = 13.1 Hz, 1H), 3.63 (s, 3H), 2.96 ( dt, J = 12.9, 8.2 Hz, 1H), 2.84 (dt, J = 12.9, 7.5 Hz, 1H), 2.51 (s, 3H), 1.94-1.74 (M, 2H), 1.63-1.38 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). ESI-MS (m / z): 432.1 [M + H] ^< +>.

2-(((Butylthio) methyl) thio) -4- (1,2-dimethyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile. 3- (1,2-Dimethyl-1H-imidazol-5-yl) -1- (thiazol-2-yl) prop-2-en-1-one (0.31 mmol, 72 mg) and 2-cyanothioacetamide ( To a suspension of EtOH (1.5 mL) containing 0.93 mmol, 93 mg, 3.0 eq) was added a few drops of piperidine. After stirring at 80 ° C. for 2 hours, EtOH was evaporated and the crude product was redissolved in CH ₃ CN. Butyl (chloromethyl) sulfane (0.62 mmol, 85.5 mg) and Et ₃ N (0.93 mmol, 94.1 mg, 130 μL) were then added and the reaction mixture was stirred at 80 ° C. for 20 minutes. Upon completion, the reaction was diluted with EtOAc and water. The organic phase was separated and the aqueous layer was extracted twice with EtOAc. The extracts were combined, washed with saturated NaCl solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give 99 mg of the planned product (77%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (d, J = 3.1 Hz, 1H), 7.85 (s, 1H), 7.56 (d, J = 3.1 Hz, 1H), 7. 37 (s, 1H), 4.49 (s, 2H), 3.60 (s, 3H), 2.72 (t, J = 7.4 Hz, 2H), 2.48 (s, 3H), 1 0.62 (p, J = 7.3 Hz, 2H), 1.40 (h, J = 7.3 Hz, 2H), 0.90 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 416.6 [M + H] ⁺ .

(E) -3- (1,2-Dimethyl-1H-imidazol-5-yl) -1- (thiazol-2-yl) prop-2-en-1-one. To a solution of 1- (thiazol-2-yl) -2- (triphenyl-λ ^5-in 6 ml of CH ₃ CN containing 1,5-dimethyl-1H-imidazole-2-carbaldehyde (2.0 mmol, 250 mg). Phosphanylidene) ethane-1-one (4.0 mmol, 1.55 g, 2.0 equiv) was added. The reaction mixture was stirred at 90 ° C. for 48 hours. Upon completion, the solvent was evaporated and the residue was purified by flash chromatography to give 331 mg of the planned product (71%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.08 (d, J = 3.0 Hz, 1H), 7.97 (d, J = 3.0 Hz, 1H), 7.90 (d, J = 15. 9 Hz, 1H), 7.76 (d, J = 15.9 Hz, 1H), 7.60 (s, 1H), 3.72 (s, 3H), 2.43 (s, 3H). ESI-MS (m / z): 234.3 [M + H] ^< +>.

2-Bromo-1- (thiazol-2-yl) ethane-1-one. n-BuLi (24.7 mL, 61.7 mmol, 2.5 M in hexane) was added dropwise to a solution of 2-diazole (5.0 g, 59 mmol) in anhydrous diethyl ether (50 mL) at -78 ° C. . After 15 minutes, ethyl bromoacetate (6.84 mL, 61.7 mmol) was added, the cold bath was removed, and the solution was allowed to warm to room temperature. The reaction mixture was treated with AcOH (7 mL) and then diluted with water (100 mL) and ether (60 mL). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was suspended in hexane and heated to reflux for 15 minutes, after which the product was decanted off leaving an impure oil. This was repeated 5 times to obtain a white solid in 88% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.05 (d, J = 3.0 Hz, 1H), 7.77 (d, J = 3.0 Hz, 1H), 4.71 (s, 2H). ESI-MS (m / z): 207.8 [M + H] ^< +>.

1- (thiazol-2-yl) -2- (triphenyl-λ ⁵ -phosphanylidene) ethane-1-one. To a solution of toluene (337.7 mL) containing 2-bromo-1- (thiazol-2-yl) ethane-1-one (10.7 g, 0.0517 mol) was added triphenylphosphine (14.1 g, 0.0539 mol). ) Was added in small portions. The mixture was stirred at room temperature for 3 hours. The yellowish precipitate was removed by filtration and washed several times with toluene and then with petroleum ether. Water was added to the precipitate and treated dropwise with 1N NaOH to pH 10 (pH 7 had a color change from yellow to orange). The mixture was stirred for 30 minutes at room temperature. The precipitate was removed by filtration and washed several times with water. The resulting orange solid was heated under vacuum at 50 ° C. to remove all the water, giving a 96% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.82 (d, J = 3.1 Hz, 1H), 7.72 (ddd, J = 12.8, 8.3, 1.4 Hz, 6H), 7.61 -7.54 (m, 3H), 7.51-7.45 (m, 6H), 7.38 (dd, J = 3.1, 1.3 Hz, 1H), 5.00 (d, J = 23.3 Hz, 1H). ESI-MS (m / z): 387.9 [M + H] ^< +>.

SW211689. Enantiomers were separated on a 1 cm Chiralpak AD column using 70% MeOH and 30% EtOH with a flow rate of 2.5 mL / min. With a 70 μL injection, the first peak was 15.2-20 minutes and the second peak was 21.4-27 minutes. Optical rotation: Peak 1 = −22.9, Peak 2 = + 47.19.

SW212345. The enantiomers were separated on a 1 cm Chiralpak AD column using 70% EtOH and 30% hexane with a flow rate of 3.5 mL / min. With a 200 μL injection, the first peak was 13-16 minutes and the second peak was 25-30 minutes. UV absorption was monitored at 315 and 254 nm. Optical rotation: Peak 1 = −43.3, Peak 2 = + 83.82.

SW2123364. The enantiomers were separated on a 1 cm Chiralpak AD column using 50% EtOH and 50% hexane with a flow rate of 2.5 mL / min. With an 80 μL injection, the first peak was 27.5-31 minutes and the second peak was 32-36 minutes. UV absorption was monitored at 315 and 254 nm. Optical rotation: Peak 1 = + 75.46, Peak 2 = −51.24.

SW208436. Enantiomers were separated on a 1 cm Chiralpak AD column using 30% EtOH and 70% Hex. With a 200 μL injection at a flow rate of 2.5 mL / min, the first peak was approximately 28-32 minutes and the second peak was approximately 35-42 minutes. UV absorption was monitored at 315 and 254 nm. Optical rotation: Peak 1 = −52.15, Peak 2 = + 65.36.

SW2122831.4- (3-Amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-4-yl) -N- (2-hydroxyethyl) benzamide. Ethanolamine (0.055 mmol, 1.1 eq) was added to SW209281 4- (3-amino-2- (butyl (11-oxydanyl) -13-sulfanyl) -6- (thiazol-2-yl) thieno [2,3 -B] Pyridin-4-yl) benzoic acid (23 mg, 0.05 mmol), HATU (23 mg, 0.06 mmol, 1.2 eq), and DMF (200 μL) were added followed by DIPEA (26 mg, 0.20 mmol, 2.0 eq.) Was added. The solution was stirred at room temperature for 3 hours, then diluted with EtOAc and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography in 92% isolated yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.01 (s, 1H), 7.94 (d, J = 8.3 Hz, 2H), 7.89 (d, J = 3.2 Hz, 1H), 7. 53 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 3.2 Hz, 1H), 6.85 (t, J = 5.6 Hz, 1H), 4.54 (s, 2H) ), 3.87 (t, J = 5.2 Hz, 2H), 3.67 (q, J = 5.6 Hz, 2H), 3.28 (ddd, J = 12.8, 9.0, 6. 1 Hz, 1H), 3.11 (ddd, J = 12.8, 9.1, 6.7 Hz, 1H), 2.64 (s, 1H), 1.80-1.63 (m, 2H), 1.56-1.41 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 501.1 [M + H] ^< +>.

SW209281 4- (3-amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-4-yl) benzoic acid. LiOH (7.9 mg, 0.329 mmol) was converted to methyl 4- (3-amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-4-yl) benzoate . To a solution of THF (214 μL), MeOH (214 μL), and H ₂ O (71 μL) containing SW209127 (50 mg, 0.11 mmol). The reaction was stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc and washed with 1M HCl. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the product in 84% isolated yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.16 (d, J = 8.4 Hz, 2H), 8.05 (s, 1H), 7.95 (d, J = 3.2 Hz, 1H), 7. 68-7.55 (m, 2H), 7.52 (d, J = 3.2 Hz, 1H), 3.40-3.24 (m, 1H), 3.24-3.04 (m, 1H) ), 1.83 to 1.65 (m, 2H), 1.55-1.37 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 458.1 [M + H] ⁺ .

SW209127. Methyl 4- (3-amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-4-yl) benzoate. t-BuOK (21.8 mg, 0.19 mmol) was converted to methyl 4- (2-(((butylsulfinyl) methyl) thio) -3-cyano-6- (thiazol-2-yl) pyridin-4-yl) benzoate DMF (1.30 mL) containing (152.8 mg, 0.32 mmol) was added and the solution was stirred at 35 ° C. for 40 minutes. The reaction mixture was diluted with EtOAc and washed several times with 10% AcOH. The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified using automated flash chromatography to give a bright green product in 66% isolated yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.19 (d, J = 7.5 Hz, 2H), 8.04 (s, 1H), 7.91 (d, J = 3.2 Hz, 1H), 7. 67-7.54 (m, 2H), 7.50 (d, J = 3.2 Hz, 1H), 3.97 (s, 3H), 3.27 (ddd, J = 12.8, 8.9) , 6.2 Hz, 1H), 3.10 (ddd, J = 12.8, 9.0, 6.8 Hz, 1H), 1.81-1.63 (m, 2H), 1.54-1. 39 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 472.1 [M + H] ^< +>.

Methyl 4- (2-(((butylsulfinyl) methyl) thio) -3-cyano-6- (thiazol-2-yl) pyridin-4-yl) benzoate is a synthetic procedure described for the preparation of analog SW209415 And prepared using methyl 4- (2-(((butylthio) methyl) thio) -3-cyano-6- (thiazol-2-yl) pyridin-4-yl) benzoate as starting material, white A solid was obtained in 98% isolated yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.15 (d, J = 8.3 Hz, 2H), 8.05 (s, 1H), 7.95 (d, J = 3.1 Hz, 1H), 7. 68 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 3.1 Hz, 1H), 4.68 (d, J = 13.1 Hz, 1H), 4.42 (d, J = 13.1 Hz, 1H), 3.91 (s, 3H), 3.01-2.86 (m, 1H), 2.87-2.74 (m, 1H), 1.88-1.72. (M, 2H), 1.55-1.35 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 472.1 [M + H] ^< +>.

Methyl 4- (2-(((butylthio) methyl) thio) -3-cyano-6- (thiazol-2-yl) pyridin-4-yl) benzoate. 2-Cyanothioacetamide (275 mg, 2.74 mmol) and methyl (E) -4- (3-oxo-3- (thiazol-2-yl) prop-1-en-1-yl) benzoate (250 mg, 0.24 mmol). the 915Mmol), evacuated and combined in a vial backfilled with _{O 2,} followed by the addition of ethanol (2.75 mL) and piperidine (2 drops). The solution was sparged with O ₂ for several minutes and then stirred at 80 ° C. for 4 hours. The solvent was evaporated and the product proceeded to the next step. Acetonitrile (2 mL) containing butyl (chloromethyl) sulfane (252.5 mg, 1.83 mmol) was added to the product from the first step followed by Et ₃ N (278 mg, 2.75 mmol). The solution was stirred at 80 ° C. for 20 minutes. The reaction mixture was diluted with EtOAc, washed with water, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude solid was purified using automated flash chromatography (80% hexane, 20% EtOAc). Product in 24% yield as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.18 (d, J = 8.4 Hz, 2H), 8.02 (s, 1H), 7.98 (d, J = 3.1 Hz, 1H), 7. 71 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 3.2 Hz, 1H), 4.52 (s, 2H), 3.95 (s, 3H), 2.76 ( t, J = 7.3 Hz, 2H), 1.64 (tt, J = 7.7, 6.3 Hz, 2H), 1.42 (h, J = 7.3 Hz, 2H), 0.91 (t J = 7.3 Hz, 3H). ESI-MS (m / z): 456.1 [M + H] ⁺ .

Methyl (E) -4- (3-oxo-3- (thiazol-2-yl) prop-1-en-1-yl) benzoate. In a dry flask, 1- (thiazol-2-yl) -2- (triphenyl-λ ⁵ -phosphanylidene) ethane-1-one (1.5 g, 3.9 mmol) and methyl 4-formylbenzoate (634 mg, 3.86 mmol) was dissolved in anhydrous chloroform (19.3 mL) and the solution was stirred at 71 ° C. overnight. The solvent was evaporated under reduced pressure and the solid precipitate was purified using automated flash chromatography (100% DCM) to give a white solid in 76% yield. ¹ H NMR (400 MHz, CDCl 3) δ 8.10-8.05 (m, 3H), 8.01 (d, J = 1.3 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H) 7.72 (d, J = 3.0 Hz, 1H), 3.93 (s, 3H). ESI-MS (m / z): 274.0 [M + H] ⁺

SW212833.4- (4- (aminomethyl) phenyl) -2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-3-amine. THF with 4- (4- (azidomethyl) phenyl) -2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-3-amine (10 mg, 0.02 mmol) PPh ₃ (6 eq) was added to the solution of and the reaction mixture was stirred overnight at room temperature. Upon completion, water was added and the reaction was stirred for an additional 5 hours at room temperature and diluted with EtOAc. The organic phase was separated and the aqueous layer was extracted twice with EtOAc. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give 7 mg of the planned product. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04 (s, 1H), 7.91 (d, J = 3.2 Hz, 1H), 7.63-7.37 (m, 5H), 4.65 ( s, 2H), 4.00 (s, 2H), 3.35-3.23 (m, 1H), 3.19-3.04 (m, 1H), 2.24 (s, 2H), 1 0.83-1.63 (m, 2H), 1.59-1.38 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 443.1 [M + H] ^< +>.

4- (4- (azidomethyl) phenyl) -2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-3-amine. SW209510 (4- (3-Amino-2- (butyl (11-oxydanyl) -13-sulfanyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-4-yl) phenyl) methanol (10 mg, 0.022 mmol) in a solution of toluene with diphenylphosphoryl azide (7.4 mg, 0.027 mmol, 1.2 eq) and 1,8-diazabicyclo [5.4.0] undec-7-ene (4 0.5 mg, 0.029 mmol, 1.3 eq) was added and the reaction was stirred overnight at room temperature. Upon completion, the reaction was diluted with EtOAc and water. The organic phase was separated and the aqueous layer was extracted twice with EtOAc. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give 10 mg of the planned product. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.05 (s, 1H), 7.92 (d, J = 3.2 Hz, 1H), 7.56-7.44 (m, 4H), 7.51 ( d, J = 3.2 Hz, 1H), 4.61 (s, 2H), 4.47 (s, 2H), 3.28 (ddd, J = 12.8, 9.0, 6.2 Hz, 1H ), 3.11 (ddd, J = 12.8, 9.0, 6.8 Hz, 1H), 1.80-1.65 (m, 2H), 1.52-1.43 (m, 2H) 0.94 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 469.1 [M + H] ⁺ .

SW209510. (4- (3-Amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-4-yl) phenyl) methanol. t-BuOK (22.8 mg, 0.20 mmol) was converted to 2-(((butylsulfinyl) methyl) thio) -4- (4- (hydroxymethyl) phenyl) -6- (thiazol-2-yl) nicotinonitrile. (150 mg, 0.34 mmol) was added to 3 times a vial, evacuated and backfilled with _{N 2,} followed by the addition of DMF (1.3 mL). The solution was sparged with N ₂ for several minutes and then heated at 32 ° C. The reaction mixture was monitored by TLC (80% EtOAc. 20% hexane) every 5 minutes and upon completion, diluted with EtOAc and washed with 10% AcOH. The organic layer was then dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The product was purified using automated flash chromatography to give an isolated green solid / oil in 16% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 (s, 1H), 7.90 (d, J = 3.2 Hz, 1H), 7.59-7.40 (m, 5H), 4.80 ( s, 2H), 4.63 (s, 2H), 3.27 (ddd, J = 12.8, 9.0, 6.1 Hz, 1H), 3.10 (ddd, J = 12.8, 9 .1, 6.6 Hz, 1H), 1.78-1.61 (m, 2H), 1.55-1.40 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H) . ESI-MS (m / z): 444.1 [M + H] ^< +>.

2-(((butylsulfinyl) methyl) thio) -4- (4- (hydroxymethyl) phenyl) -6- (thiazol-2-yl) nicotinonitrile. Chloroform (2.5 mL), acetic acid (1.4 mL), and hydrogen peroxide (108.0 μL, 1.06 mmol, 30% aqueous solution) were combined with 2-(((butylthio) methyl) thio) -4- (4- (Hydroxymethyl) phenyl) -6- (thiazol-2-yl) nicotinonitrile was added. The solution was stirred at 32 ° C. for 45 minutes. The reaction mixture was then diluted with EtOAc, washed with saturated NaHCO ₃ , the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the desired product in 94% yield. . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (s, 1H), 7.93 (d, J = 3.1 Hz, 1H), 7.59 (d, J = 8.2 Hz, 2H), 7. 55 (d, J = 3.1 Hz, 1H), 7.48 (d, J = 7.9 Hz, 2H), 4.73 (s, 2H), 4.66 (d, J = 13.1 Hz, 1H ), 4.38 (d, J = 13.1 Hz, 1H), 2.93 (dt, J = 13.0, 8.1 Hz, 1H), 2.79 (dt, J = 13.0, 7.H). 2 Hz, 1H), 1.84-1.72 (m, 2H), 1.55-1.33 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 444.1 [M + H] ^< +>.

2-((((Butylthio) methyl) thio) -4- (4- (hydroxymethyl) phenyl) -6- (thiazol-2-yl) nicotinonitrile. Methyl 4- (2-(((butylthio) methyl) thio) -3-cyano-6- (thiazol-2-yl) pyridin-4-yl) benzoate (336 mg, 0.74 mmol) in THF (8.41 mL) LiBH ₄ (96.3 mg, 4.42 mmol) was added to the solution of 0) at 0 ° C. The reaction was stirred at room temperature for 36 hours and the reaction was monitored by LC / MS. The reaction mixture was diluted with EtOAc and water. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the product in 96% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 (s, 1H), 7.98 (d, J = 3.1 Hz, 1H), 7.65 (d, J = 8.1 Hz, 2H), 7. 56 (d, J = 3.1 Hz, 1H), 7.52 (d, J = 8.0 Hz, 2H), 4.79 (d, J = 4.3 Hz, 2H), 4.52 (s, 2H) ), 2.75 (t, J = 7.4 Hz, 2H), 1.71-1.58 (m, 2H), 1.49-1.33 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H). ESI-MS (m / z): 428.1 [M + H] ⁺ .

SW212834.4- (3-Amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-4-yl) benzyl (2- (dimethylamino) ethyl) carbamate Was prepared using the synthetic procedure described for the preparation of analog SW209415. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04 (s, 1H), 7.91 (d, J = 3.2 Hz, 1H), 7.66-7.38 (m, 5H), 5.62 ( s, 1H), 5.19 (s, 2H), 4.63 (s, 2H), 3.40-3.22 (m, 3H), 3.11 (ddd, J = 12.8, 9. 0, 6.8 Hz, 1H), 2.50 (t, J = 5.9 Hz, 2H), 2.28 (s, 6H), 1.79-1.64 (m, 2H), 1.39- 1.57 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 558.1 [M + H] ⁺ .

4- (2-(((butylsulfinyl) methyl) thio) -3-cyano-6- (thiazol-2-yl) pyridin-4-yl) benzyl (2- (dimethylamino) ethyl) carbamate Prepared using the synthetic procedure described for the preparation of SW209415. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.09 (s, 1H), 7.99 (d, J = 3.1 Hz, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7. 58 (d, J = 3.1 Hz, 1H), 7.52 (d, J = 8.2 Hz, 2H), 6.03 (t, J = 5.7 Hz, 1H), 5.16 (s, 2H) ), 4.74 (d, J = 13.1 Hz, 1H), 4.39 (d, J = 13.1 Hz, 1H), 3.37 (q, J = 5.6 Hz, 2H), 2.97 (Dt, J = 12.9, 8.2 Hz, 1H), 2.82 (dt, J = 12.9, 7.3 Hz, 1H), 2.60 (t, J = 5.9 Hz, 2H), 2.34 (s, 6H), 1.90-1.74 (m, 2H), 1.61-1.36 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 558.1 [M + H] ⁺ .

4- (2-(((Butylthio) methyl) thio) -3-cyano-6- (thiazol-2-yl) pyridin-4-yl) benzyl (2- (dimethylamino) ethyl) carbamate. Triphosgene (6.0 mg, 0.02 mmol, 0.35 eq) was weighed into an oven-dried vial. Dichloromethane (100 μL) was added followed by pyridine (4.6 mg, 0.058 mmol, 1.0 eq) at 0 ° C. 2-((((Butylthio) methyl) thio) -4- (4- (hydroxymethyl) phenyl) -6- (thiazol-2-yl) nicotinonitrile (25 mg, 0.058 mmol, 1.0 eq) was added to DCM. (100 μL) and added to the triphosgene solution. The reaction was gradually warmed to ambient temperature and stirred overnight. The reaction was quenched with water, extracted with DCM (3 ×), dried over MgSO ₄ , filtered and concentrated to give benzyl chloroformate. The crude product was redissolved in dichloromethane and excess N, N-dimethylethylenediamine was added. The reaction was stirred at room temperature for 2 hours. Upon completion, the reaction was diluted with dichloromethane and water. The organic phase was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give 7 mg of the planned product. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.00 (s, 1H), 7.97 (d, J = 3.1 Hz, 1H), 7.67-7.60 (m, 2H), 7.56 ( d, J = 3.1 Hz, 1H), 7.53-7.48 (m, 2H), 5.63 (s, 1H), 5.16 (s, 2H), 4.51 (s, 2H) 3.33 (q, J = 5.7 Hz, 2H), 2.74 (t, J = 7.3 Hz, 2H), 2.51 (t, J = 5.9 Hz, 2H), 2.29 ( s, 6H), 1.70-1.55 (m, 2H), 1.49-1.34 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 542.1 [M + H] ^< +>.
Synthesis of SW21835:

2- (4- (3-Amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-4-yl) phenoxy) acetic acid. Following the hydrolysis procedure described using analog SW209281, methyl 2- (4- (3-amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridine The corresponding acid was formed in quantitative yield using -4-yl) phenoxy) acetate (SW212365, PCT / US2014 / 060761) as starting material. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.01-7.82 (m, 2H), 7.77-7.64 (m, 1H), 7.43 (d, J = 8.0 Hz, 2H) 7.10 (d, J = 8.2 Hz, 2H), 4.76 (s, 2H), 3.29 (s, 2H), 3.26-3.17 (m, 1H), 3.16 -2.98 (m, 1H), 1.76-1.55 (m, 2H), 1.53-1.41 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H) . ESI-MS (m / z): 488.1 [M + H] ^< +>.

SW21835. N-allyl-2- (4- (3-amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-4-yl) phenoxy) acetamide is analogous 2- (4- (3-Amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b]) using the amide bond coupling procedure used for isomer SW213210 Prepared using pyridin-4-yl) phenoxy) acetic acid as starting material and allylamine as substrate. The crude material was purified using automated chromatography to give 43% isolated yield. ¹ H NMR (400 MHz, chloroform-d) δ 8.01 (s, 1H), 7.91 (d, J = 1.7 Hz, 1H), 7.52-7.42 (m, 3H), 7.07 (D, J = 8.2 Hz, 2H), 6.72-6.59 (m, 1H), 5.88 (ddt, J = 16.5, 10.8, 5.6 Hz, 1H), 5. 26-5.13 (m, 2H), 4.66 (s, 2H), 4.59 (s, 2H), 4.01 (t, J = 5.9 Hz, 2H), 3.34-3. 23 (m, 1H), 3.16-3.06 (m, 1H), 1.79-1.66 (m, 2H), 1.53-1.42 (m, 2H), 0.94 ( t, J = 7.3 Hz, 3H). ESI-MS (m / z): 527.1 [M + H] ⁺ .

SW212836.2- (Butylsulfonyl) -4- (1,2-dimethyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-3-amine. The title compound was formed as a byproduct in the final cyclization step for the synthesis of SW209415. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.08 (s, 1H), 7.95 (d, J = 3.2 Hz, 1H), 7.55 (d, J = 3.2 Hz, 1H), 7. 16 (s, 1H), 5.31 (s, 2H), 3.41 (s, 3H), 3.24-3.18 (m, 2H), 2.51 (s, 3H), 1.87 -1.73 (m, 2H), 1.49-1.36 (m, 2H), 0.95-0.85 (t, J = 7.0 Hz, 3H). ESI-MS (m / z): 448.1 [M + H] ⁺ .

SW213061. N- (4- (3-Amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-4-yl) benzyl) acetamide was prepared from analog SW209415. Was prepared using the synthetic procedure described for. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 8.01 (s, 1H), 7.89 (d, J = 3.1 Hz, 1H), 7.53 (d, J = 3.2 Hz, 1H), 7.47-7.41 (m, 4H), 6.25 (s, 1H), 4.59 (s, 2H), 4.50 (d, J = 6.1 Hz, 2H), 3.23 ( ddd, J = 13.0, 9.2, 6.1 Hz, 1H), 3.08 (ddd, J = 12.9, 9.2, 6.5 Hz, 1H), 2.03 (s, 3H) 1.57-1.86 (m, 2H), 1.57-1.35 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 485.1 [M + H] ^< +>.

N- (4- (2-(((butylsulfinyl) methyl) thio) -3-cyano-6- (thiazol-2-yl) pyridin-4-yl) benzyl) acetamide is described for the preparation of analog SW209415. Prepared using the synthetic procedure ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.07 (s, 1H), 7.98 (d, J = 3.1 Hz, 1H), 7.61 (d, J = 8.2 Hz, 2H), 7. 58 (d, J = 3.1 Hz, 1H), 7.43 (d, J = 8.1 Hz, 2H), 6.04 (t, J = 6.3 Hz, 1H) 4.70 (d, J = 13.1 Hz, 1H), 4.50 (d, J = 5.9 Hz, 2H), 4.39 (d, J = 13.1 Hz, 1H), 2.96 (dt, J = 13.0, 8 .1 Hz, 1H), 2.81 (dt, J = 12.9, 7.3 Hz, 1H), 2.05 (s, 3H), 1.91-1.73 (m, 2H), 1.62 -1.37 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). ESI-MS (m / z): 485.1 [M + H] ^< +>.

N- (4- (2-(((butylthio) methyl) thio) -3-cyano-6- (thiazol-2-yl) pyridin-4-yl) benzyl) acetamide. To a solution of 4- (4- (aminomethyl) phenyl) -2-(((butylthio) methyl) thio) -6- (thiazol-2-yl) nicotinonitrile (30 mg, 0.07 mmol) in THF, Acetic anhydride (21.4 mg, 0.21 mmol, 3.0 eq) and pyridine (16.6 mg, 0.21 mmol, 3.0 eq) were added and the reaction was stirred at 50 ° C. overnight. When complete, the reaction was diluted with EtOAc and water. The organic phase was separated and the aqueous layer was extracted twice with EtOAc. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give 33 mg of the planned product. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.9 (s, 1H), 7.97 (d, J = 3.1 Hz, 1H), 7.61 (d, J = 8.2 Hz, 2H), 7. 56 (d, J = 3.2 Hz, 1H), 7.43 (d, J = 8.1 Hz, 2H), 5.95 (s, 1H), 4.51 (s, 2H), 4.49 ( d, J = 5.9 Hz, 2H), 2.74 (t, J = 7.3 Hz, 2H), 2.04 (s, 3H), 1.72-1.54 (m, 2H), 1. 49-1.32 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 469.1 [M + H] +.

4- (4- (Aminomethyl) phenyl) -2-(((butylthio) methyl) thio) -6- (thiazol-2-yl) nicotinonitrile. 4- (4- (azidomethyl) phenyl) -2-(((butylthio) methyl) thio) -6- (thiazol-2-yl) nicotinonitrile according to the standard procedure for Staudinger reduction (with respect to SW21833) As the starting material. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.01 (s, 1H), 7.97 (d, J = 3.1 Hz, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7. 55 (d, J = 3.2 Hz, 1H), 7.47 (d, J = 8.2 Hz, 2H), 4.51 (s, 2H), 3.96 (s, 2H), 2.75 ( t, J = 7.3 Hz, 2H), 2.47 (s, 2H), 1.72-1.52 (m, 2H), 1.42 (h, J = 7.3 Hz, 2H),. 90 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 427.1 [M + H] +.

4- (4- (Azidomethyl) phenyl) -2-(((butylthio) methyl) thio) -6- (thiazol-2-yl) nicotinonitrile. According to standard procedures for the preparation of azides from alcohols (for SW21833), 2-(((butylthio) methyl) thio) -4- (4- (hydroxymethyl) phenyl) -6- (thiazol-2-yl) nicoti Nononitrile is used as the starting material. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 (s, 1H), 7.98 (d, J = 3.1 Hz, 1H), 7.67 (d, J = 7.5 Hz, 2H), 7. 57 (d, J = 3.1 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H), 4.52 (s, 2H), 4.44 (s, 2H), 2.75 ( t, J = 7.4 Hz, 2H), 1.69-1.58 (m, 2H), 1.50-1.35 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H ). ESI-MS (m / z): 453.1 [M + H] +.

SW213062.1- (4- (3-amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-4-yl) benzyl) -3-ethylurea Prepared using the synthetic procedure described for the preparation of analog SW209415. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) 7.95 (s, 1H), 7.86 (d, J = 3.1 Hz, 1H), 7.50 (d, J = 3.1 Hz, 1H), 7.46-7.30 (m, 4H), 5.43 (s, 1H), 4.98 (s, 1H), 4.59 (s, 2H), 4.41 (d, J = 6. 1 Hz, 2H), 3.32-3.13 (m, 3H), 3.14-3.00 (m, 1H), 1.92-1.57 (m, 2H), 1.57-1. 37 (m, 2H), 1.11 (t, J = 7.2 Hz, 1H), 0.93 (t, J = 7.3 Hz, 1H). ESI-MS (m / z): 514.1 [M + H] ^< +>.

1- (4- (2-(((Butylsulfinyl) methyl) thio) -3-cyano-6- (thiazol-2-yl) pyridin-4-yl) benzyl) -3-ethylurea is synthesized by analog SW209415. Prepared using the synthetic procedure described for the preparation of ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 (s, 1H), 7.99 (d, J = 3.1 Hz, 1H), 7.68-7.52 (m, 3H), 7.44 ( d, J = 7.9 Hz, 2H), 4.94 (s, 1H), 4.79 (s, 1H), 4.70 (d, J = 13.1 Hz, 1H), 4.45 (s, 2H), 4.38 (d, J = 13.1 Hz, 1H), 3.23 (q, J = 7.2 Hz, 2H), 2.96 (dt, J = 12.9, 8.1 Hz, 1H) ), 2.81 (dt, J = 12.9, 7.3 Hz, 1H), 1.96-1.74 (m, 2H), 1.67-1.37 (m, 2H), 1.14 (T, J = 7.2 Hz, 3H), 0.95 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 514.1 [M + H] ^< +>.

1- (4- (2-(((Butylthio) methyl) thio) -3-cyano-6- (thiazol-2-yl) pyridin-4-yl) benzyl) -3-ethylurea. To a solution of 4- (4- (aminomethyl) phenyl) -2-(((butylthio) methyl) thio) -6- (thiazol-2-yl) nicotinonitrile (50 mg, 0.117 mmol) in THF Ethyl acid (13 mg, 0.23 mmol, 19 μl) was added at 0 ° C. The reaction was stirred at room temperature for 1 hour. During this time, solid formation occurred which was filtered off, washed with a small amount of EtOAc and finally dried under reduced pressure to give 40 mg of product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.13-8.02 (m, 2H), 7.91 (s, 1H), 7.73-7.61 (m, 2H), 7.49- 7.37 (m, 2H), 6.40 (t, J = 6.1 Hz, 1H), 5.94 (t, J = 5.6 Hz, 1H), 4.62 (s, 2H), 4. 27 (d, J = 6.0 Hz, 2H), 3.02 (q, J = 6.8 Hz, 2H), 2.68 (t, J = 7.5 Hz, 2H), 1.66 to 1.45 (M, 2H), 1.41-1.20 (m, 2H), 0.98 (t, J = 6.9 Hz, 3H), 0.82 (t, J = 7.4 Hz, 3H). ESI-MS (m / z): 498.1 [M + H] ^< +>.

SW213064.4- (3-Amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-4-yl) benzyl (2-chloroethyl) carbamate Prepared using the synthetic procedure described for the preparation of SW209415. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 8.11-7.99 (m, 2H), 7.98-7.84 (m, 1H), 7.60-7.42 (m, 4H), 5.32 (s, 2H), 5.21 (s, 2H), 4.59 (s, 1H), 3.65 (t, J = 5.7 Hz, 2H), 3.60-3.47 ( m, 2H), 3.25 (ddd, J = 13.0, 9.0, 6.0 Hz, 1H), 3.10 (ddd, J = 12.9, 9.1, 6.6 Hz, 1H) 1.81-1.60 (m, 2H), 1.58-1.37 (m, 2H), 0.94 (t, J = 7.3 Hz, 2H). ESI-MS (m / z): 550.1 [M + H] ^< +>.

4- (2-(((Butylsulfinyl) methyl) thio) -3-cyano-6- (thiazol-2-yl) pyridin-4-yl) benzyl (2-chloroethyl) carbamate was prepared for the preparation of analog SW209415. Prepared using the synthetic procedure described. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.09 (s, 1H), 7.99 (d, J = 3.1 Hz, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7. 59 (d, J = 3.1 Hz, 1H), 7.52 (d, J = 8.0 Hz, 2H), 5.25 (s, 1H), 5.18 (s, 2H), 4.72 ( d, J = 13.1 Hz, 1H), 4.39 (d, J = 13.1 Hz, 1H), 3.75-3.42 (m, 4H), 2.97 (dt, J = 12.9) , 8.1 Hz, 1H), 2.82 (dt, J = 12.8, 7.3 Hz, 1H), 1.94-1.73 (m, 2H), 1.59-1.38 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 550.1 [M + H] ^< +>.

4- (2-(((Butylthio) methyl) thio) -3-cyano-6- (thiazol-2-yl) pyridin-4-yl) benzyl (2-chloroethyl) carbamate. To a solution of 2-(((butylthio) methyl) thio) -4- (4- (hydroxymethyl) phenyl) -6- (thiazol-2-yl) nicotinonitrile (50 mg, 0.12 mmol) in THF was added. -Chloroethyl isocyanate (24 mg, 0.23 mmol, 20 μl, 2.0 eq) and pyridine (28 mg, 0.35 mmol, 30 μl, 3.0 eq) were added at 0 ° C. The reaction was stirred at 50 ° C. overnight. When complete, the reaction was diluted with EtOAc and water. The organic phase was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give 40 mg of product. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.09-7.93 (m, 2H), 7.74-7.61 (m, 2H), 7.56 (d, J = 3.1 Hz, 1H), 7.55-7.46 (m, 2H), 5.18 (s, 2H), 4.52 (s, 2H), 3.83-3.39 (m, 4H), 2.75 (t, J = 7.5 Hz, 2H), 1.80-1.53 (m, 2H), 1.42 (h, J = 7.4 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H) ). ESI-MS (m / z): 534.1 [M + H] ⁺ .

SW213065.4- (3-Amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-4-yl) benzylethylcarbamate was prepared for the preparation of analog SW213064. Prepared using the synthetic procedure described. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.97-7.83 (m, 2H), 7.75-7.64 (m, 1H), 7.62-7.41 (m, 4H), 5 .17 (s, 2H), 3.24 (ddd, J = 12.1, 5.9, 3.1 Hz, 1H), 3.15 (q, J = 7.5 Hz, 2H), 3.07 ( ddd, J = 12.4, 6.5, 3.0 Hz, 1H), 1.78-1.55 (m, 2H), 1.56-1.38 (m, 2H), 1.11 (t , J = 7.2 Hz, 3H), 0.94 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 515.1 [M + H] ⁺ .

SW213066.2- (4- (3-amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-4-yl) phenyl) ethan-1-ol According to the reduction procedure for analog SW213153, methyl 2- (4- (3-amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridine-4- Prepared using yl) phenyl) acetate (SW213150) as starting material. The crude reaction mixture was purified using automated chromatography (100% EtOAc) to give 30% isolated yield. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 8.06 (s, 1H), 7.92 (d, J = 3.2 Hz, 1H), 7.53 (d, J = 3.2 Hz, 1H), 7.47-7.39 (m, 4H), 3.91 (t, J = 6.6 Hz, 2H), 3.28-3.20 (m, 1H), 3.15-3.05 (m) 1H), 2.96 (t, J = 6.6 Hz, 2H), 1.75-1.63 (m, 2H), 1.55-1.42 (m, 2H), 0.94 (t J = 7.3 Hz, 3H). ESI-MS (m / z): 458.1 [M + H] ⁺ .
Synthesis of SW213150:

(E) -3- (4-Iodophenyl) -1- (thiazol-2-yl) prop-2-en-1-one. CH ₃ CN (0.35M) was replaced with 1- (thiazol-2-yl) -2- (triphenyl-15-phosphanylidene) ethan-1-one (1.67 g, 4.31 mmol) and 4-iodobenzaldehyde (1 0.0 g, 4.3 mmol). The mixture was heated at 90 ° C. for 48 hours and then concentrated under reduced pressure. The crude mixture was dissolved in CHCl ₃ and concentrated under reduced pressure (repeated 3 times) and then purified. The crude reaction mixture was purified using automated chromatography (100% DCM) to recover 30% isolated product. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.05 (d, J = 3.0 Hz, 1 H), 7.92 (d, J = 6.3 Hz, 2 H), 7.75 (d, J = 8.4 Hz) 2H), 7.70 (d, J = 3.0 Hz, 1H), 7.41 (d, J = 8.4 Hz, 2H). ESI-MS (m / z): 341.9 [M + H] ^< +>.

2-((((Butylthio) methyl) thio) -4- (4-iodophenyl) -6- (thiazol-2-yl) nicotinonitrile. (E) -3- (4-Iodophenyl) -1- (thiazol-2-yl) prop-2-en-1-one (200 mg, 0.586 mmol) and 2-cyanothioacetamide (176 mg, 1.76 mmol) ) Was purged with oxygen three times followed by the addition of EtOH (1.76 mL) and piperidine (cat). The reaction mixture was bubbled with oxygen and then heated at 80 ° C. for 4 hours. The mixture was concentrated and the crude material was used in the next step without purification. Thion was alkylated similar to analog SW209415 using butyl (chloromethyl) sulfane as the alkylating reagent. The crude mixture was purified twice using automated chromatography (first 10% EtOAc and 90% Hex, then 100% DCM). The isolation yield after the two steps was 30%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.01-7.94 (m, 2H), 7.87 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 3.1 Hz, 1H ), 7.38 (d, J = 8.5 Hz, 2H), 4.51 (s, 2H), 2.75 (t, J = 7.3 Hz, 2H), 1.70-1.57 (m) 2H), 1.49-1.34 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 524.0 [M + H] ⁺ .

Methyl 2- (4- (2-(((butylthio) methyl) thio) -3-cyano-6- (thiazol-2-yl) pyridin-4-yl) phenyl) acetate. 2-(((Butylthio) methyl) thio) -4- (4-iodophenyl) -6- (thiazol-2-yl) nicotinonitrile (114 mg, 0.218 mmol), Pd ₂ (dba) ₃ (52 mg, 0.057 mmol), tri- (2-furyl) -phosphine (46 mg, 0.20 mmol), and 4Å molecular sieves (700 mg) were combined in a 4 ml vial and this vial was charged with argon. Dry and degassed diisopropylamine (1.5 ml) and t-butoxyl acetylene (1.6 ml, 0.8 M diethyl ether solution) were added sequentially to the reaction vial at room temperature. The reaction was stirred overnight and this was monitored by TLC (eluent: EtOAc: Hex = 1: 5). As soon as the iodide was consumed, the reaction mixture was added to an aluminum oxide (Blockman I, basic, active) column and the desired fraction was eluted with 300 ml EtOAc: Hex = 1: 10. MeOH (4 mL) was added to the desired concentrated fraction and stirred at 70 ° C. overnight. Upon completion, the reaction was concentrated under reduced pressure and purified using automated chromatography (20% EtOAc, 80% Hex) to give 36% isolated yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.01 (s, 1H), 7.97 (d, J = 3.1 Hz, 1H), 7.62 (d, J = 7.5 Hz, 2H), 7. 55 (d, J = 3.1 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 4.51 (s, 2H), 3.71 (s, 3H), 3.70 ( s, 2H), 2.74 (t, J = 7.5 Hz, 2H), 1.69-1.57 (m, 2H), 1.49-1.34 (m, 2H), 0.90 ( t, J = 7.3 Hz, 3H).

Methyl 2- (4- (2-(((butylsulfinyl) methyl) thio) -3-cyano-6- (thiazol-2-yl) pyridin-4-yl) phenyl) acetate is analogous to analog SW209415. According to the synthetic oxidation procedure, methyl 2- (4- (2-(((butylthio) methyl) thio) -3-cyano-6- (thiazol-2-yl) pyridin-4-yl) phenyl) acetate as starting material Prepared using. The reaction gave a 96% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.08 (s, 1H), 7.97 (d, J = 3.1 Hz, 1H), 7.62 (d, J = 8.2 Hz, 2H), 7. 57 (d, J = 3.2 Hz, 1H), 7.45 (d, J = 8.3 Hz, 2H), 4.72 (d, J = 13.1 Hz, 1H), 4.39 (d, J = 13.1 Hz, 1H), 3.71 (s, 3H), 3.70 (s, 2H), 3.02-2.89 (m, 1H), 2.86-2.76 (m, 1H) ), 1.8-1.75 (m, 2H), 1.57-1.39 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). ESI-MS (m / z): 486.1 [M + H] ^< +>.

SW213150. Methyl 2- (4- (3-amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-4-yl) phenyl) acetate. tBu-OK (5 mg, 0.05 mmol) was added to methyl 2- (4- (2-(((butylsulfinyl) methyl) thio) -3-cyano-6- (thiazol-2-yl) pyridin-4-yl. ) Phenyl) acetate (37 mg, 0.075 mmol) was added and the reagent was purged with N ₂ three times. DMF (300 μL) was added and N ₂ was bubbled through the solution and then heated at 35 ° C. for 5-10 minutes. Upon completion, the reaction was diluted with EtOAc and washed with a 10% aqueous solution of AcOH and then several times with water. The organic layer was then dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified using automated chromatography (50% EtOAc, 50% hexane) to give 71% isolated yield. ¹ H NMR (400 MHz, CD ₃ ) ₂ CO) δ 8.00 (s, 1H), 7.96 (d, J = 3.2 Hz, 1H), 7.79 (d, J = 3.2 Hz, 1H) 7.61-7.49 (m, 4H), 3.80 (s, 2H), 3.68 (s, 3H), 3.22-3.13 (m, 1H), 3.11-3 .01 (m, 1H), 1.76-1.61 (m, 2H), 1.54-1.37 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 486.1 [M + H] ^< +>.

SW213153.2-((4- (3-amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-4-yl) benzyl) oxy) ethane-1 -All. Methyl 2-((4- (3-amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-4-yl) benzyl) oxy) acetate (5 mg, LiBH ₄ (0.0582 mmol, 6.0 eq) was added to a solution of THF containing 0.0097 mmol) and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc and _{H 2} O. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 1.6 mg of product. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.00 (s, 1H), 7.94 (d, J = 3.2 Hz, 1H), 7.75 (d, J = 3.2 Hz, 1H), 7 .60 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 7.9 Hz, 2H), 4.68 (s, 2H), 3.77-3.70 (m, 2H) 3.68-3.60 (m, 2H), 3.36-3.22 (m, 1H), 3.11 (ddd, J = 12.7, 9.3, 6.2 Hz, 1H), 1.79-1.58 (m, 2H), 1.56-1.44 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 488.1 [M + H] ^< +>.

Methyl 2-((4- (3-amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-4-yl) benzyl) oxy) acetate. Methyl 2-((4- (2-(((butylsulfinyl) methyl) thio) -3-cyano-6- (thiazol-2-yl) pyridin-4-yl) benzyl) oxy) acetate (6 mg, 0. The vial containing 013 mmol) was evacuated three times and backfilled with N ₂ before adding DMF (100 μL). The solution was stirred under N ₂ for 10 minutes before tBuOK (0.0058 mmol, 10 μL of DMF solution containing 0.65 mg) was added. The reaction mixture was stirred at room temperature under N ₂ for 5-10 minutes (reaction was monitored by TLC). Upon completion, the reaction was diluted with EtOAc, washed with 5% AcOH, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified using automated flash chromatography to give 5 mg. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.9 (s, 1H), 7.94 (d, J = 3.2 Hz, 1H), 7.75 (d, J = 3.2 Hz, 1H), 7 .60 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 7.8 Hz, 2H), 4.72 (s, 2H), 4.24 (s, 2H), 3.75 (S, 3H), 3.36-3.21 (m, 1H), 3.11 (ddd, J = 12.8, 9.3, 6.2 Hz, 1H), 1.85-1.57 ( m, 2H), 1.57-1.41 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 516.1 [M + H] ⁺ .

Methyl 2-((4- (2-(((butylsulfinyl) methyl) thio) -3-cyano-6- (thiazol-2-yl) pyridin-4-yl) benzyl) oxy) acetate is synthesized by analog SW209415. Prepared using the synthetic procedure described for the preparation of ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (s, 1H), 7.99 (d, J = 3.2 Hz, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7. 59 (d, J = 3.1 Hz, 1H), 7.55 (d, J = 8.4 Hz, 2H), 4.74 (d, J = 13.1 Hz, 1H), 4.71 (s, 2H) ), 4.39 (d, J = 13.1 Hz, 1H), 4.17 (s, 2H), 3.78 (s, 3H), 2.97 (dt, J = 13.1, 8.2 Hz) 1H), 2.82 (dt, J = 12.9, 7.4 Hz, 1H), 1.91-1.77 (m, 2H), 1.55-1.40 (m, 2H), 0 .95 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 516.1 [M + H] ⁺ .

Methyl 2-((4- (2-(((butylthio) methyl) thio) -3-cyano-6- (thiazol-2-yl) pyridin-4-yl) benzyl) oxy) acetate. To a solution of 2-(((butylthio) methyl) thio) -4- (4- (hydroxymethyl) phenyl) -6- (thiazol-2-yl) nicotinonitrile (20 mg, 0.047 mmol) in THF was added NaH. (2.44 mg, 0.061 mmol, 60% dispersion in mineral oil) was added at 0 ° C. After stirring for 20 minutes at 0 ° C., methyl 2-bromoacetate (9.3 mg, 0.061 mmol) was added. The reaction mixture was stirred overnight at room temperature (the reaction did not proceed after 2 hours). The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over Mg ₂ SO ₄ , filtered and concentrated. The crude product was purified using automated flash chromatography to give 4 mg. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06-8.00 (m, 1H), 7.98 (d, J = 3.1 Hz, 1H), 7.65 (d, J = 7.9 Hz, 2H ), 7.56 (d, J = 3.2 Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H), 4.71 (s, 2H), 4.23 (s, 2H), 4.16 (s, 2H), 3.76 (s, 3H), 2.76 (t, J = 7.4 Hz, 2H), 1.73-1.51 (m, 2H), 1.42 ( h, J = 7.4 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 500.1 [M + H] ^< +>.

SW213154.2- (Butylsulfinyl) -4- (2-chloro-1-methyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) thieno [2,3-b] pyridine-3- The amine was prepared using the synthetic procedure described for the preparation of analog SW209415. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 8.09 (s, 1H), 7.94 (d, J = 3.2 Hz, 1H), 7.56 (d, J = 3.2 Hz, 1H), 7.16 (s, 1H), 4.70 (s, 2H), 3.45 (s, 3H), 3.33-3.18 (m, 1H), 3.18-2.98 (m, 1H), 1.84-1.63 (m, 2H), 1.56-1.40 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 453.1 [M + H] ⁺ .

2-(((Butylsulfinyl) methyl) thio) -4- (2-chloro-1-methyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile is converted to analog SW209415. Prepared using the synthetic procedure described for the preparation of ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.9 (d, J = 3.1 Hz, 1H), 7.96 (s, 1H), 7.61 (d, J = 3.1 Hz, 1H), 7. 43 (s, 1H), 4.69 (d, J = 13.1 Hz, 1H), 4.42 (d, J = 13.0 Hz, 1H), 3.69 (s, 3H), 2.95 ( dt, J = 12.9, 8.1 Hz, 1H), 2.83 (dt, J = 12.8, 7.0 Hz, 1H), 1.83 (p, J = 7.7 Hz, 2H), 1 .59-1.40 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 453.1 [M + H] ⁺ .

2-(((Butylthio) methyl) thio) -4- (2-chloro-1-methyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile was synthesized from analog SW209415. Prepared using the synthetic procedure described for preparation. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (d, J = 3.2 Hz, 1H), 7.88 (s, 1H), 7.59 (d, J = 3.2 Hz, 1H), 7. 39 (s, 1H), 4.50 (s, 2H), 3.68 (s, 3H), 2.74 (t, J = 7.4 Hz, 2H), 1.70-1.58 (m, 2H), 1.49-1.33 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 437.1 [M + H] ⁺ .

(E) -3- (2-Chloro-1-methyl-1H-imidazol-5-yl) -1- (thiazol-2-yl) prop-2-en-1-one was converted to 1- (thiazol-2). Wittig reaction described for the preparation of analog SW209415 from -yl) -2- (triphenyl-λ ⁵ -phosphanylidene) ethane-1-one and 2-chloro-1-methyl-1H-imidazole-5-carbaldehyde Prepared using standard procedures for. ESI-MS (m / z): 254.1 [M + H] ^< +>.

SW213155.2- (Butylsulfinyl) -4- (2-methoxy-1-methyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) thieno [2,3-b] pyridine-3- Amine. SW213154- (Butylsulfinyl) -4- (2-chloro-1-methyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-3-amine Excess NaOMe was added to a solution of 100 μL methanol containing (5 mg, 0.011 mmol) and the reaction mixture was heated at 80 ° C. for 30 min. The reaction was diluted with EtOAc, acidified with 5% aqueous AcOH to pH 7, the organic phase was separated and the aqueous layer was extracted twice with EtOAc. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified on TLC to give the planned product, 0.98 mg of product. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.09 (s, 1H), 7.97 (d, J = 3.2 Hz, 1H), 7.58 (d, J = 3.2 Hz, 1H), 6 .87 (s, 1H), 4.12 (s, 3H), 3.43-3.23 (m, 1H), 3.31 (s, 3H), 3.22-3.02 (m, 1H) ), 1.83 to 1.62 (m, 2H), 1.64 to 1.46 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 448.1 [M + H] ⁺ .
Synthesis of SW213156:

(E) -1,3-di (thiazol-2-yl) prop-2-en-1-one. CH ₃ CN (0.35M) was replaced with 1- (thiazol-2-yl) -2- (triphenyl-λ5-phosphanylidene) ethan-1-one (1.72 g, 4.42 mmol) and 2-thiazolecarboxaldehyde. (500 mg, 4.42 mmol) was added to the vial. The mixture was heated at 90 ° C. for 24 hours and then concentrated under reduced pressure. The crude material was dissolved in CHCl ₃ and concentrated under reduced pressure (repeated 3 times) and then purified. The enone was purified using automated chromatography (60% EtOAc, 40% Hex) to give 67% isolated yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.12 (s, 2H), 8.06 (d, J = 3.0 Hz, 1H), 7.97 (d, J = 3.2 Hz, 1H), 7. 72 (d, J = 3.0 Hz, 1H), 7.48 (d, J = 3.2 Hz, 1H). ESI-MS (m / z): 223.0 [M + H] ^< +>.

2-(((((2-methoxyethyl) thio) methyl) thio) -4,6-di (thiazol-2-yl) nicotinonitrile. A vial containing (E) -1,3-di (thiazol-2-yl) prop-2-en-1-one (200 mg, 0.897 mmol) and 2-cyanothioacetamide (135 mg, 1.35 mmol), Purge with oxygen three times followed by addition of EtOH (2.0 mL) containing tBuOK (101 mg, 0.897 mmol). The reaction mixture was bubbled with oxygen and heated at 80 ° C. for 4 hours and then concentrated. The crude product was carried on to the next step after a standard alkylation procedure similar to analog SW209415 using (chloromethyl) (2-methoxyethyl) sulfane as the alkylating reagent. The crude mixture was purified twice using automated chromatography (first 3% MeOH and 97% DCM, then 40% EtOAc and 60% Hex) to give 27% isolated yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.45 (s, 1H), 8.10 (d, J = 3.2 Hz, 1H), 8.00 (d, J = 3.1 Hz, 1H), 7. 64 (d, J = 3.1 Hz, 1H), 7.57 (d, J = 3.1 Hz, 1H), 4.57 (s, 2H), 3.66 (t, J = 6.1 Hz, 2H) ), 3.36 (s, 3H), 2.92 (t, J = 6.1 Hz, 2H). ESI-MS (m / z): 407.0 [M + H] ⁺ .

2-(((((2-methoxyethyl) sulfinyl) methyl) thio) -4,6-di (thiazol-2-yl) nicotinonitrile. The sulfide was converted to methyl 2-((((2-methoxyethyl) thio) methyl) thio) -4,6-di (thiazol-2-yl) nicotinonitrile using the procedure described for analog SW209415. Oxidized using as starting material. The reaction gave a 97% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.52 (s, 1H), 8.12 (d, J = 3.2 Hz, 1H), 8.02 (d, J = 3.1 Hz, 1H), 7. 66 (d, J = 3.1 Hz, 1H), 7.60 (d, J = 3.1 Hz, 1H), 4.77 (d, J = 12.9 Hz, 1H), 4.61 (d, J = 13.0 Hz, 1 H), 3.99 (ddd, J = 10.3, 6.2, 3.8 Hz, 1 H), 3.80 (ddd, J = 10.9, 8.1, 3.3 Hz) 1H), 3.38 (s, 3H), 3.17 (ddd, J = 13.7, 8.0, 3.7 Hz, 1H), 3.05 (ddd, J = 13.8, 6. 2, 3.3 Hz, 1 H). ESI-MS (m / z): 423.0 [M + H] ^< +>.

SW213156.2-((2-methoxyethyl) sulfinyl) -4,6-di (thiazol-2-yl) thieno [2,3-b] pyridin-3-amine. KOH (1.9 mg, 0.034 mmol, 0.6 eq, 2.0 M aqueous solution) was added to 2-((((2-methoxyethyl) sulfinyl) methyl) thio) -4,6-di (thiazole-2- Yl) Nicotinonitrile (24 mg, 0.057) was added to a solution of DMF (248 μl) / MeOH (124 μl). The reaction mixture was stirred at 32 ° C. for 5 minutes. Upon completion, the reaction was diluted with EtOAc and washed with 10% aqueous AcOH. The organic phase was washed several times with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified using automated chromatography to isolate the desired product as a 69% red solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.48 (s, 1H), 8.01 (d, J = 3.3 Hz, 1H), 7.96 (d, J = 3.1 Hz, 1H), 7. 60 (d, J = 3.3 Hz, 1H), 7.52 (d, J = 3.1 Hz, 1H), 3.88-3.81 (m, 1H), 3.70-3.55 (m 2H), 3.38 (s, 3H), 3.31-3.22 (m, 1H). ESI-MS (m / z): 423.0 [M + H] ^< +>.

SW213208.2- (Butylsulfinyl) -4- (1,2-dimethyl-1H-imidazol-5-yl) -6- (5-methylthiazol-2-yl) thieno [2,3-b] pyridine-3 The amine was prepared in 46% isolated yield using the synthetic procedure described for the preparation of analog SW209415. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 7.9 (s, 1H), 7.58 (q, J = 1.1 Hz, 1H), 7.06 (s, 1H), 4.72 (s, 2H), 3.38 (s, 3H), 3.24 (ddd, J = 12.8, 9.0, 6.2 Hz, 1H), 3.10 (ddd, J = 12.8, 9.0) , 6.6 Hz, 1 H), 2.55 (d, J = 1.2 Hz, 3 H), 2.45 (s, 3 H), 1.84 to 1.58 (m, 2 H), 1.58-1. .38 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 446.1 [M + H] ⁺ .

2-(((butylsulfinyl) methyl) thio) -4- (1,2-dimethyl-1H-imidazol-5-yl) -6- (5-methylthiazol-2-yl) nicotinonitrile Prepared in 94% isolated yield using the synthetic procedure described for the preparation of SW209415. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85 (s, 1H), 7.62 (q, J = 1.0 Hz, 1H), 7.39 (s, 1H), 4.70 (d, J = 13.1 Hz, 1 H), 4.36 (d, J = 13.1 Hz, 1 H), 3.61 (s, 3 H), 2.96 (dt, J = 12.9, 8.1 Hz, 1 H), 2.80 (dt, J = 12.9, 7.0 Hz, 1H), 2.55 (d, J = 1.1 Hz, 3H), 2.47 (s, 3H), 1.88-1.77 (M, 2H), 1.57-1.40 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 446.1 [M + H] ⁺ .

2-(((Butylthio) methyl) thio) -4- (1,2-dimethyl-1H-imidazol-5-yl) -6- (5-methylthiazol-2-yl) nicotinonitrile is synthesized by analog SW209415. Prepared in 39% isolated yield using the synthetic procedure described for the preparation of ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.78 (s, 1H), 7.61 (s, 1H), 7.36 (s, 1H), 4.48 (s, 2H), 3.60 (s 3H), 2.74 (t, J = 7.3 Hz, 2H), 2.55 (s, 3H), 2.47 (s, 3H), 1.68-1.54 (m, 2H), 1.49-1.35 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 430.1 [M + H] ^< +>.

(E) -3- (1,2-Dimethyl-1H-imidazol-5-yl) -1- (5-methylthiazol-2-yl) prop-2-en-1-one. To a solution of 1 ml of CH ₃ CN containing 1,5-dimethyl-1H-imidazole-2-carbaldehyde (62 mg, 0.5 mmol) was added 1- (5-methylthiazol-2-yl) -2- (triphenyl). -Λ ⁵ -phosphanylidene) ethane-1-one (0.5 mmol, 200 mg, 1.0 eq) was added. The reaction mixture was stirred at 90 ° C. for 48 hours. The solvent was evaporated and the residue was purified by flash chromatography to give 41 mg of the planned product. ESI-MS (m / z): 248.1 [M + H] ^< +>.

1- (5-Methylthiazol-2-yl) -2- (triphenyl-λ ⁵ -phosphanylidene) ethane-1-one. To a solution of 2-chloro-1- (5-methylthiazol-2-yl) ethanone (340 mg, 1.94 mmol) in toluene (13 mL) was added triphenylphosphine (531 mg, 2.03 mmol). The mixture was stirred at 80 ° C. for 2 hours. The precipitate was removed by filtration and washed several times with toluene and then with petroleum ether. The solid was dissolved in water and the solution was treated dropwise with 1N NaOH to pH 10. The mixture was stirred for 10 minutes at room temperature. The precipitate was removed by filtration and washed several times with water to give 200 mg of product. ESI-MS (m / z): 401.1 [M + H] ^< +>.

2-Chloro-1- (5-methylthiazol-2-yl) ethanone. Isopropylmagnesium chloride (2M Et ₂ O solution, 2.67 mL, 5.35 mmol) dropwise with THF containing 2-bromo-5-methylthiazole (1.0 g, 5.62 mmol, 1.05 eq) ( 10 mL) solution at 0 ° C. The resulting solution was stirred at 0 ° C. for 15 minutes. A solution of 2-chloro-1-morpholinoethanone (959 mg, 5.88 mmol, 1.1 eq) in THF (3 mL) was added dropwise and the mixture was stirred at 0 ° C. for 45 min, then 1. Stir for 5 hours. The reaction was quenched by the addition of saturated aqueous NH ₄ Cl and the mixture was diluted with diethyl ether. The phases were separated and the aqueous phase was extracted with diethyl ether. The organic layers were combined, washed with water and saturated aqueous NaHCO ₃ , dried over MgSO ₄ and concentrated to give 2-chloro-1- (5-methylthiazol-2-yl) ethanone. The crude product was purified in 36% isolated yield using automated flash chromatography. ESI-MS (m / z): 176.1 [M + H] ^< +>.

SW2133209.1- (4- (3-Amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-4-yl) benzyl) -3- (2- Hydroxyethyl) urea was converted to 4- (4- (aminomethyl) phenyl) -2-(((butylthio) methyl) thio) -6- (thiazol-2-yl) nicotinonitrile and triphosgene (1.0 eq) From the synthetic procedure described for the preparation of analog SW212834. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 7.97 (s, 1H), 7.87 (d, J = 3.2, 1H), 7.50 (d, J = 3.2, 1H), 7.45-7.32 (m, 4H), 5.61 (t, J = 6.1 Hz, 1H), 5.37 (t, J = 5.8 Hz, 1H), 4.61 (s, 2H) ), 4.41 (d, J = 5.9 Hz, 2H), 3.61 (t, J = 4.9 Hz, 2H), 3.53 (s, 1H), 3.29 (q, J = 5) .1 Hz, 2H), 3.22 (ddd, J = 13.1, 6.7, 2.1 Hz, 1H), 3.09 (ddd, J = 12.8, 9.2, 6.4 Hz, 1H) ) 1.77-1.57 (m, 2H), 1.54-1.37 (m, 2H), 0.92 (t, J = 7.3, 3H). ESI-MS (m / z): 530.1 [M + H] ⁺ .

SW213132. N- (4- (3-amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-4-yl) benzyl) -2- (dimethylamino) acetamide . SW21833 in HATU (9.5 mg, 0.025 mmol), N, N-dimethylglycine hydrochloride (3.5 mg, 0.25 mmol), and DIPEA (7.8 μL, 0.45 mmol) dissolved in DMF (60 μL). Add to 4- (4- (aminomethyl) phenyl) -2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-3-amine (10 mg, 0.023 mmol) did. The reaction mixture was stirred at room temperature overnight, then diluted with EtOAc and washed with water. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The crude product is purified first using flash chromatography (5% MeOH, 95% DCM) followed by preparative thin layer chromatography (10% MeOH, 90% DCM) and isolated to 18% Yield was obtained. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 8.06 (s, 1H), 7.92 (d, J = 3.2 Hz, 1H), 7.67 (s, 1H), 7.54 (d, J = 3.2 Hz, 1H), 7.47 (m, 4H), 4.60 (s, 2H), 4.56 (d, J = 6.3 Hz, 2H), 3.31-3.20 ( m, 1H), 3.15-3.05 (m, 1H), 3.02 (s, 2H), 2.32 (s, 6H), 1.75-1.66 (m, 2H), 1 0.52-1.42 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 528.2 [M + H] ⁺ .

SW2131321. N- (4- (3-amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-4-yl) benzyl) -2-methoxyacetamide. The title compound was prepared using the amide bond coupling procedure for SW213210 using SW21833 as the starting material and methoxyacetic acid as the coupling reagent. The crude product was purified using preparative thin layer chromatography (5% MeOH, 95% DCM) to give 18% isolated yield. ¹ H NMR (400 MHz, methylene CD ₂ Cl ₂ ) δ 8.06 (s, 1H), 7.92 (d, J = 3.2 Hz, 1H), 7.54 (d, J = 3.2 Hz, 1H) 7.53-7.43 (m, 4H), 6.99 (s, 1H), 4.59 (s, 2H), 4.58 (d, J = 6.3 Hz, 2H), 3.96. (S, 2H), 3.44 (s, 3H), 3.29-3.20 (m, 1H), 3.15-3.04 (m, 1H), 1.76-1.62 (m 2H), 1.51-1.42 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 515.1 [M + H] ⁺ .

SW213132. N- (4- (3-amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-4-yl) benzyl) methanesulfonamide. SW212833 4- (4- (aminomethyl) phenyl) -2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-3-amine (10 mg, 0.023 mmol). Suspended in DCM (300 μL) and Et ₃ N (3.5 μL, 0.025) and cooled to 0 ° C. under N ₂ . Methanesulfonyl chloride (1.8 μL, 0.023 mmol) was added to the reaction mixture, which was stirred at room temperature for 4 hours, after which one additional equivalent of methanesulfonyl chloride was added. After stirring overnight, the reaction mixture was diluted with EtOAc, washed with water and line, and the organic layer was separated. This was dried over sodium sulfate, concentrated under reduced pressure, purified using first automated chromatography (3% MeOH, 97% DCM) followed by preparative thin layer chromatography (100% EtOAc), A 3% isolated yield was obtained. ¹ H NMR (400 MHz, (CD ₃ ) ₂ CO) δ 8.02 (s, 1H), 7.99 (d, J = 3.1 Hz, 1H), 7.82 (d, J = 3.2 Hz, 1H) ), 7.65 (q, J = 8.1 Hz, 4H), 4.84 (d, J = 10.5 Hz, 2H), 4.46 (d, J = 5.2 Hz, 2H), 3.23 -3.13 (m, 1H), 3.12-3.02 (m, 1H), 2.93 (s, 3H), 1.76-1.63 (m, 2H), 1.55-1 .41 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 521.1 [M + H] ^< +>.

SW213132.2- (4- (3-Amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-4-yl) phenyl) propan-2-ol. SW209127 THF containing methyl 4- (3-amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-4-yl) benzoate (15 mg, 0.031 mmol) To a stirred solution of (500 μL) of −78 ° C., CH ₃ Li · LiBr (1.5 M ether solution, 104 μL, 0.156 mmol) is added and the reaction mixture is stirred for 3 hours, after which an additional 2 equivalents of CH ₃ Li · LiBr was added. After an additional hour, the reaction was quenched with water and diluted with EtOAc. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified using automated chromatography (4% MeOH, 96% DCM) to give 25% isolated yield. ¹ H NMR (400 MHz, (CD ₃ ) ₂ CO) δ 8.03 (s, 1H), 7.98 (d, J = 3.2 Hz, 1H), 7.81 (d, J = 3.2 Hz, 1H ), 7.77 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 8.1 Hz, 2H), 4.86 (d, J = 10.2 Hz, 2H), 3.25 -3.13 (m, 1H), 3.11-3.01 (m, 1H), 1.76-1.63 (m, 2H), 1.59 (s, 6H), 1.53-1 .40 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 472.1 [M + H] ^< +>.

Resolution of racemic SW209125 on HPLC. The enantiomers are separated on a 1 × 25 cm Chiralpak AD column using 40% iPrOH and 60% Hex using a flow rate of 2.5 mL / min, 150 μL injection, the first peak is 15 minutes The second peak was 22 minutes. Optical rotation: Peak 1 [α] +131 (c = 0.2, EtOH), Peak 2 [α] -112 (c = 0.2, EtOH).

Synthesis of inhibitors of 15-PGDH SW217778 1- (4- (3-amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-4-yl) phenyl ) Ethan-1-ol as the starting material 2-(((butylsulfinyl) methyl) thio) -4- (4- (1-hydroxyethyl) phenyl) -6- (thiazol-2-yl) nicotino Prepared from nitrile, 75%, using the synthetic procedure for analog SW209415. ¹ H NMR (400 MHz, (CD ₃ ) ₂ CO) δ 8.02 (s, 1H), 7.98 (d, J = 3.2 Hz, 1H), 7.81 (d, J = 3.1 Hz, 1H ), 7.64 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 5.02-4.96 (m, 1H), 4.88 (s) 2H), 4.47 (s, 1H), 3.26-3.14 (m, 1H), 3.14-3.01 (m, 1H), 1.83-1.62 (m, 2H) ), 1.57-1.41 (m, 2H), 1.49 (d, J = 6.5 Hz, 3H) 0.93 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 458.1 [M + H] ⁺ .

2-((((Butylsulfinyl) methyl) thio) -4- (4- (1-hydroxyethyl) phenyl) -6- (thiazol-2-yl) nicotinonitrile is converted to 2-(((butylthio) methyl) Preparation of analog SW209415 in quantitative yield via H ₂ O ₂ oxidation of thio) -4- (4- (1-hydroxyethyl) phenyl) -6- (thiazol-2-yl) nicotinonitrile Was prepared using the synthetic procedure described for. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (s, 1H), 7.99 (d, J = 3.1 Hz, 1H), 7.65 (d, J = 8.3 Hz, 2H), 7. 60 (d, J = 3.1 Hz, 1H), 7.55 (d, J = 8.3 Hz, 2H), 4.99 (q, J = 6.5 Hz, 1H), 4.73 (d, J = 13.1 Hz, 1 H), 4.40 (d, J = 13.1 Hz, 1 H), 2.98 (dt, J = 12.9, 8.1 Hz, 1 H), 2.82 (dt, J = _{12.9,7.4Hz, 1H), 2.1 (s} br, 1H), 1.90-1.74 (m, 2H), 1.54 (d, J = 6.5Hz, 3H), 1 .52-1.41 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 458.1 [M + H] ⁺ .

2-((((Butylthio) methyl) thio) -4- (4- (1-hydroxyethyl) phenyl) -6- (thiazol-2-yl) nicotinonitrile. 2-(((Butylthio) methyl) thio) -4- (4-formylphenyl) -6- (thiazole-2) obtained by dissolving methylmagnesium bromide (3.0 M ether solution, 0.071 mmol) in THF (400 μL). -Yl) To nicotinonitrile was added at -78 ° C. The reaction mixture was stirred for 3 hours, then quenched with water and extracted with EtOAc. The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified using automated chromatography (40% EtOAc, 60% Hex) to give 62% desired product. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04 (s, 1H), 7.98 (d, J = 3.1 Hz, 1H), 7.65 (d, J = 8.3 Hz, 2H), 7. 57 (d, J = 3.1 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 4.99 (q, J = 6.5 Hz, 1H), 4.53 (s, 2H _{), 2.77 (t, J =} 7.3Hz, 2H), 2.01-1.88 (s br, 1H), 1.73-1.59 (m, 2H), 1.54 (d, J = 6.4 Hz, 3H), 1.50-1.36 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 442.1 [M + H] ^< +>.

2-((((Butylthio) methyl) thio) -4- (4-formylphenyl) -6- (thiazol-2-yl) nicotinonitrile. 2-((((Butylthio) methyl) thio) -4- (4- (hydroxymethyl) phenyl) -6- (thiazol-2-yl) nicotinonitrile (Patent: WO2015 / 65716A1, 2015) (30 mg, 0 To a solution of 1.3 mL DCM containing 0.07 mmol) was added MnO ₂ (63 mg, 0.70 mmol, 10 eq). The reaction mixture was stirred at room temperature for 24 hours. Upon completion, filtered over celite and washed with DCM, the filtrate was concentrated under reduced pressure to give the pure product in 87% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.10 (s, 1H), 8.11-8.01 (m, 3H), 7.99 (d, J = 3.2 Hz, 1H), 7.81 ( d, J = 7.8 Hz, 2H), 7.59 (d, J = 3.2 Hz, 1H), 4.52 (s, 2H), 2.75 (t, J = 7.6 Hz, 2H), 1.78-1.56 (m, 2H), 1.55-1.31 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 426.1 [M + H] ⁺ .

SW217779.2- (Butylsulfinyl) -4- (1,2-dimethyl-1H-imidazol-5-yl) -6- (4-methylthiazol-2-yl) thieno [2,3-b] pyridine-3 The amine to 2-(((butylsulfinyl) methyl) thio) -4- (1,2-dimethyl-1H-imidazol-5-yl) -6- (4-methylthiazol-2-yl) nicotinonitrile Was prepared using the synthetic procedure described for the preparation of analog SW209415 in 91% isolated yield. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 8.04 (s, 1H), 7.12 (s, 1H), 7.08 (s, 1H), 4.75 (s, 2H), 3.40 (S, 3H), 3.26 (ddd, J = 13.1, 8.9, 6.2 Hz, 1H), 3.11 (ddd, J = 12.9, 8.9, 6.5 Hz, 1H) ), 2.50 (s, 3H), 2.47 (s, 3H), 1.79-1.64 (m, 2H), 1.57-1.42 (m, 2H), 0.95 ( t, J = 7.3 Hz, 3H). ESI-MS (m / z): 446.1 [M + H] ⁺ .

2-(((Butylsulfinyl) methyl) thio) -4- (1,2-dimethyl-1H-imidazol-5-yl) -6- (4-methylthiazol-2-yl) nicotinonitrile H ₂ O ₂ oxidation of (((butylthio) methyl) thio) -4- (1,2-dimethyl-1H-imidazol-5-yl) -6- (4-methylthiazol-2-yl) nicotinonitrile Via the synthetic procedure described for the preparation of analog SW209415 in 94% isolated yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.91 (s, 1H), 7.41 (s, 1H), 7.16 (s, 1H), 4.71 (d, J = 13.2 Hz, 1H) 4.47 (d, J = 13.1 Hz, 1H), 3.63 (s, 3H), 3.03-2.83 (m, 2H), 2.52 (s, 3H), 2.51 (S, 3H), 1.91-1.70 (m, 2H), 1.61-1.36 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). ESI-MS (m / z): 446.1 [M + H] ⁺ .

2-(((Butylthio) methyl) thio) -4- (1,2-dimethyl-1H-imidazol-5-yl) -6- (4-methylthiazol-2-yl) nicotinonitrile is obtained as (E) -3- (1,2-dimethyl-1H-imidazol-5-yl) -1- (4-methylthiazol-2-yl) prop-2-en-1-one, 2-cyanoethanethioamide and butyl (chloro Prepared from methyl) sulfane in 86% isolated yield using the synthetic procedure described for the preparation of analog SW209415. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.86 (s, 1H), 7.38 (s, 1H), 7.15 (s, 1H), 4.51 (s, 2H), 3.63 (s 3H), 2.77 (t, J = 7.4 Hz, 2H), 2.53 (s, 3H), 2.51 (s, 3H), 1.73-1.55 (m, 2H), 1.52-1.32 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 430.1 [M + H] ^< +>.

(E) -3- (1,2-Dimethyl-1H-imidazol-5-yl) -1- (4-methylthiazol-2-yl) prop-2-en-1-one was converted to 1- (4- 58% isolation from methylthiazol-2-yl) -2- (triphenyl-λ5-phosphanylidene) ethane-1-one and 1,2-dimethyl-1H-imidazole-5-carbaldehyde via Wittig reaction Prepared in yield using the synthetic procedure described for the preparation of analog SW209415. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.78 (d, J = 15.8, 1H), 7.71 (d, J = 15.9 Hz, 1H), 7.64 (s, 1H), 7. 24 (q, J = 1.0 Hz, 1H), 3.67 (s, 3H), 2.55 (d, J = 0.9 Hz, 3H), 2.48 (s, 3H). ESI-MS (m / z): 248.1 [M + H] ^< +>.

1- (4-Methylthiazol-2-yl) -2- (triphenyl-λ5-phosphanylidene) ethane-1-one was prepared using the synthetic procedure described for the preparation of analog SW209415. ESI-MS (m / z): 402.1 [M + H] ^< +>.

SW217780.2- (butylsulfinyl) -4- (1-methyl-1H-pyrazol-5-yl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-3-amine is converted to 2 27% via the cyclization of-(((butylsulfinyl) methyl) thio) -4- (1-methyl-1H-pyrazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile Prepared in isolated yield using the synthetic procedure described for the preparation of analog SW209415. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 8.14 (s, 1H), 7.96 (d, J = 3.1 Hz, 1H), 7.63 (d, J = 1.9 Hz, 1H), 7.58 (d, J = 3.2 Hz, 1H), 6.51 (s, 1H), 4.61 (s, 2H), 3.74 (s, 3H), 3.26 (ddd, J = 12.8, 8.8, 6.4 Hz, 1H), 3.20-3.02 (m, 1H), 1.74 (p, J = 7.8 Hz, 2H), 1.50 (h, J = 7.3, 2.3 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 418.1 [M + H] ^< +>.

2-((((Butylsulfinyl) methyl) thio) -4- (1-methyl-1H-pyrazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile is converted to 2-(((butylthio) 48% isolated yield via H ₂ O ₂ oxidation of methyl) thio) -4- (1-methyl-1H-pyrazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile Prepared using the synthetic procedure described for the preparation of analog SW209415. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 (s, 1H), 8.01 (dJ = 3.1, 1H), 7.63 (d, J = 3.1 Hz, 1H), 7.62 ( s, 1H), 6.67 (d, J = 2.1 Hz, 1H), 4.71 (d, J = 13.1 Hz, 1H), 4.43 (d, J = 13.2 Hz, 1H), 3.97 (s, 3H), 2.97 (dt, J = 12.9, 8.1 Hz, 1H), 2.84 (dt, J = 13.1, 7.3 Hz, 1H), 1.84 (H, J = 7.3, 6.8 Hz, 2H), 1.64-1.37 (m, 2H), 0.97 (d, J = 7.3, 3H). ESI-MS (m / z): 418.1 [M + H] ^< +>.

2-(((Butylthio) methyl) thio) -4- (1-methyl-1H-pyrazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile is converted to (E) -3- (1 56% isolated yield from -methyl-1H-pyrazol-5-yl) -1- (thiazol-2-yl) prop-2-en-1-one, 2-cyanoethanethioamide and butyl (chloromethyl) sulfane Prepared using the synthetic procedure described for the preparation of analog SW209415. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.00 (d, J = 3.1 Hz, 1H), 7.97 (s, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7. 60 (d, J = 3.1 Hz, 1H), 6.64 (d, J = 2.0 Hz, 1H), 4.52 (s, 2H), 3.96 (s, 3H), 2.77 ( t, J = 7.3 Hz, 2H), 1.80-1.50 (m, 2H), 1.50-1.31 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H ). ESI-MS (m / z): 402.1 [M + H] +.

(E) -3- (1-Methyl-1H-pyrazol-5-yl) -1- (thiazol-2-yl) prop-2-en-1-one is substituted with 1- (thiazol-2-yl)- For the preparation of analog SW209415 from 2- (triphenyl-λ5-phosphanylidene) ethane-1-one and 1-methyl-1H-pyrazole-5-carbaldehyde via the Wittig reaction in 62% isolated yield Prepared using the synthetic procedure described. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.05 (d, J = 3.0 Hz, 1 H), 7.89 (d, J = 15.7 Hz, 1 H), 7.79 (d, J = 15.8 Hz) 1H), 7.71 (d, J = 3.0 Hz, 1H), 7.49 (d, J = 2.2 Hz, 1H), 6.78 (d, J = 2.2 Hz, 1H), 4 .02 (s, 3H). ESI-MS (m / z): 220.0 [M + H] ^< +>.

SW217781.2- (butylsulfinyl) -4- (1-methyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-3-amine is converted to 2 91% via the cyclization of-(((butylsulfinyl) methyl) thio) -4- (1-methyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile Prepared in isolated yield using the synthetic procedure described for the preparation of analog SW209415. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 8.12 (s, 1H), 7.96 (d, J = 3.2 Hz, 1H), 7.67 (s, 1H), 7.57 (d, J = 3.2 Hz, 1H), 7.23 (d, J = 1.1 Hz, 1H), 4.65 (s, 2H), 3.53 (s, 3H), 3.26 (ddd, J = 12.8, 8.9, 6.5 Hz, 1H), 3.12 (ddd, J = 12.8, 8.9, 6.9 Hz, 1H), 1.85-1.67 (m, 2H) 1.58-1.40 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 418.1 [M + H] ^< +>.

The two enantiomers of SW217781 can be separated by chiral HPLC: 2 × 25 cm Chiralpak OD-H column using 100% EtOH with a flow rate of 10 mL / min, 600 μL injection. The first peak was 15.5 minutes and the second peak was 22.5 minutes. Optical rotation: Peak 1 [α] -101 (c = 0.17, EtOH), Peak 2 [α] +95 (c = 0.19, EtOH).

2-((((Butylsulfinyl) methyl) thio) -4- (1-methyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile is converted to 2-(((butylthio) Methyl) thio) -4- (1-methyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile via H ₂ O ₂ oxidation in 89% isolated yield Prepared using the synthetic procedure described for the preparation of analog SW209415. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (d, J = 3.4 Hz, 1H), 7.98 (s, 1H), 7.70 (s, 1H), 7.61 (d, J = 3.1 Hz, 1H), 7.55 (s, 1H), 4.69 (d, J = 13.1 Hz, 1H), 4.42 (d, J = 13.1 Hz, 1H), 3.78 ( s, 3H), 2.96 (dt, J = 12.9, 8.1 Hz, 1H), 2.83 (dt, J = 13.0, 7.0 Hz, 1H), 1.83 (p, J = 7.7 Hz, 2H), 1.59-1.37 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 418.1 [M + H] ^< +>.

2-(((Butylthio) methyl) thio) -4- (1-methyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile is converted to (E) -3- (1 73% isolated yield from -methyl-1H-imidazol-5-yl) -1- (thiazol-2-yl) prop-2-en-1-one, 2-cyanoethanethioamide and butyl (chloromethyl) sulfane Prepared using the synthetic procedure described for the preparation of analog SW209415. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (d, J = 3.1 Hz, 1H), 7.90 (s, 1H), 7.67 (s, 1H), 7.58 (d, J = 3.1 Hz, 1H), 7.51 (s, 1H), 4.50 (s, 2H), 3.76 (s, 3H), 2.76 (t, J = 7.3 Hz, 2H), 1 .74-1.54 (m, 2H), 1.42 (h, J = 7.3 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 402.1 [M + H] ^< +>.

(E) -3- (1-Methyl-1H-imidazol-5-yl) -1- (thiazol-2-yl) prop-2-en-1-one is substituted with 1- (thiazol-2-yl)- Using the synthetic procedure described for the preparation of analog SW209415 from 2- (triphenyl-λ5-phosphanylidene) ethane-1-one and 1-methyl-1H-imidazole-5-carbaldehyde via the Wittig reaction Prepared. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 (d, J = 3.0 Hz, 1 H), 7.84 (d, J = 15.9 Hz, 1 H), 7.74 (d, J = 15.9 Hz) 1H), 7.68 (d, J = 3.0 Hz, 1H), 7.68 (s, 1H), 7.56 (s, 1H), 3.79 (s, 3H). ESI-MS (m / z): 220.1 [M + H] ^< +>.

SW217782.2- (butylsulfinyl) -4- (1-methyl-1H-1,2,3-triazol-5-yl) -6- (thiazol-2-yl) thieno [2,3-b] pyridine- 3-Amine was converted to 2-(((butylsulfinyl) methyl) thio) -4- (1-methyl-1H-1,2,3-triazol-5-yl) -6- (thiazol-2-yl) nicoti Prepared using the synthetic procedure described for the preparation of analog SW209415 in 39% isolated yield via nitrile cyclization reaction. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 8.13 (s, 1H), 7.97 (d, J = 3.1 Hz, 1H), 7.90 (s, 1H), 7.59 (d, J = 3.1 Hz, 1H), 4.40 (s, 2H), 3.96 (s, 3H), 3.27 (ddd, J = 13.0, 8.3, 6.7 Hz, 1H), 3.12 (dt, J = 13.0, 7.9 Hz, 1H), 1.76-1.70 (m, 2H), 1.54-1.47 (m, 2H), 0.96 (t J = 7.3 Hz, 3H). ESI-MS (m / z): 419.1 [M + H] ⁺ .

2-(((butylsulfinyl) methyl) thio) -4- (1-methyl-1H-1,2,3-triazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile -(((Butylthio) methyl) thio) -4- (1-methyl-1H-1,2,3-triazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile H ₂ O ₂ Prepared using the synthetic procedure described for the preparation of analog SW209415 in 61% isolated yield via oxidation. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.05 (s, 1H), 8.04 (s, 1H), 8.03 (d, J = 3.1 Hz, 1H), 7.66 (d, J = 3.1 Hz, 1H), 4.69 (d, J = 13.2 Hz, 1H), 4.48 (d, J = 13.2 Hz, 1H), 4.18 (s, 3H), 2.97 ( dt, J = 12.8, 8.1 Hz, 1H), 2.91-2.76 (m, 1H), 1.85 (p, J = 7.7 Hz, 2H), 1.56-1.44 (M, 2H), 0.96 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 419.1 [M + H] ⁺ .

2-((((Butylthio) methyl) thio) -4- (1-methyl-1H-1,2,3-triazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile ) -3- (1-Methyl-1H-1,2,3-triazol-5-yl) -1- (thiazol-2-yl) prop-2-en-1-one, 2-cyanoethanethioamide and butyl Prepared from (chloromethyl) sulfane in 46% isolated yield using the synthetic procedure described for the preparation of analog SW209415. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 (s, 1H), 8.01 (d, J = 3.1 Hz, 1H), 7.96 (s, 1H), 7.63 (d, J = 3.1, 1H), 4.53 (s, 2H), 4.17 (s, 3H), 2.77 (t, J = 7.3 Hz, 3H), 1.76-1.49 (m, 2H), 1.49-1.35 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 403.1 [M + H] +.

(E) -3- (1-Methyl-1H-1,2,3-triazol-5-yl) -1- (thiazol-2-yl) prop-2-en-1-one is substituted with 1- (thiazole 2-yl) -2- (triphenyl-λ5-phosphanylidene) ethane-1-one and 1-methyl-1H-1,2,3-triazole-5-carbaldehyde via the Wittig reaction Prepared using the synthetic procedure described for the preparation of SW209415. ESI-MS (m / z): 221.1 [M + H] ^< +>.

SW217976.2- (Butylsulfinyl) -4- (oxazol-4-yl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-3-amine is converted to 2-(((butylsulfinyl For the preparation of analog SW209415 in 61% isolated yield via cyclization of methyl) thio) -4- (oxazol-4-yl) -6- (thiazol-2-yl) nicotinonitrile Prepared using the synthetic procedure described. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 8.34 (d, J = 1.0 Hz, 1 H), 8.29 (s, 1 H), 8.18 (d, J = 1.0 Hz, 1 H), 7.96 (d, J = 3.2 Hz, 1H), 7.57 (d, J = 3.1 Hz, 1H), 6.41 (s, 2H), 3.39-3.21 (m, 1H) ), 3.12 (ddd, J = 12.8, 9.3, 6.3 Hz, 1H), 1.86-1.66 (m, 2H), 1.57-1.40 (m, 2H) 0.95 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 405.1 [M + H] ⁺ .

2-((((Butylsulfinyl) methyl) thio) -4- (oxazol-4-yl) -6- (thiazol-2-yl) nicotinonitrile is converted to 2-(((butylthio) methyl) thio) -4. Synthetic procedure described for the preparation of analog SW209415 in 78% isolated yield via H ₂ O ₂ oxidation of-(oxazol-4-yl) -6- (thiazol-2-yl) nicotinonitrile It was prepared using. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.71 (s, 1H), 8.66 (s, 1H), 8.05 (s, 1H), 8.01 (d, J = 3.1 Hz, 1H) 7.59 (d, J = 3.1 Hz, 1H), 4.70 (d, J = 13.1 Hz, 1H), 4.42 (d, J = 13.1 Hz, 1H), 2.95 ( dt, J = 13.0, 8.2 Hz, 1H), 2.82 (dt, J = 13.0, 7.3 Hz, 1H), 1.82 (p, J = 7.6 Hz, 2H), 1 .58-1.37 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 405.1 [M + H] ⁺ .

2-(((Butylthio) methyl) thio) -4- (oxazol-4-yl) -6- (thiazol-2-yl) nicotinonitrile is converted to (E) -3- (oxazol-4-yl)- Describes the preparation of analog SW209415 in 67% isolated yield from 1- (thiazol-2-yl) prop-2-en-1-one, 2-cyanoethanethioamide and butyl (chloromethyl) sulfane. Prepared using synthetic procedures. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.69 (d, J = 0.9 Hz, 1 H), 8.56 (s, 1 H), 8.03 (d, J = 0.9 Hz, 1 H), 7. 99 (d, J = 3.1 Hz, 1H), 7.55 (d, J = 3.1 Hz, 1H), 4.49 (s, 2H), 2.74 (t, J = 7.3 Hz, 2H) ) 1.77-1.53 (m, 2H), 1.53-1.32 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 389.1 [M + H] ^< +>.

(E) -3- (oxazol-4-yl) -1- (thiazol-2-yl) prop-2-en-1-one was converted to 1- (thiazol-2-yl) -2- (triphenyl- λ5-phosphanylidene) ethane-1-one 1.3 equivalents and oxazole-4-carbaldehyde are described for the preparation of analog SW209415 via a Wittig reaction in CH ₃ CN at 90 ° C. for 20 hours. Prepared using synthetic procedures. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.09 (d, J = 15.6 Hz, 1 H), 8.05 (d, J = 3.0 Hz, 1 H), 7.95 (s, 1 H), 7. 93 (s, 1H), 7.87 (d, J = 15.7 Hz, 1H), 7.69 (d, J = 3.0 Hz, 1H). ESI-MS (m / z): 207.1 [M + H] ^< +>.

SW217937.2- (Butylsulfinyl) -4- (4-methylthiazol-2-yl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-3-amine is converted to 2-(( (82% isolated yield) via cyclization of (butylsulfinyl) methyl) thio) -4- (4-methylthiazol-2-yl) -6- (thiazol-2-yl) nicotinonitrile, Prepared using the synthetic procedure described for the preparation of analog SW209415. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 8.49 (s, 1H), 7.98 (d, J = 3.2 Hz, 1H), 7.58 (d, J = 3.2 Hz, 1H), 7.22 (s, 1H), 6.88 (s, 2H), 3.28 (ddd, J = 12.7, 9.2, 5.8 Hz, 1H), 3.14 (ddd, J = 12) .8, 9.3, 6.4 Hz, 1H), 2.57 (s, 3H), 1.88-1.66 (m, 2H), 1.61-1.40 (m, 2H), 0 .96 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 435.1 [M + H] ⁺ .

2-((((Butylsulfinyl) methyl) thio) -4- (4-methylthiazol-2-yl) -6- (thiazol-2-yl) nicotinonitrile is converted to 2-(((butylthio) methyl) thio. Preparation of analog SW209415 in 96% isolated yield via H ₂ O ₂ oxidation of) -4- (4-methylthiazol-2-yl) -6- (thiazol-2-yl) nicotinonitrile Was prepared using the synthetic procedure described for. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.54 (s, 1H), 8.03 (d, J = 3.1 Hz, 1H), 7.61 (d, J = 3.1 Hz, 1H), 7. 23 (s, 1H), 4.74 (d, J = 13.1 Hz, 1H), 4.37 (d, J = 13.1 Hz, 1H), 2.97 (dt, J = 13.0, 8 .2 Hz, 1 H), 2.81 (dt, J = 13.0, 7.3 Hz, 1 H), 2.58 (s, 3 H), 1.83 (p, J = 7.6 Hz, 2 H), 1 .56-1.44 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 435.1 [M + H] ⁺ .

2-(((Butylthio) methyl) thio) -4- (4-methylthiazol-2-yl) -6- (thiazol-2-yl) nicotinonitrile is converted to (E) -3- (4-methylthiazole 2-yl) -1- (thiazol-2-yl) prop-2-en-1-one, 2-cyanoethanethioamide and butyl (chloromethyl) sulfane in 57% isolated yield in analog SW209415 Prepared using the synthetic procedure described for the preparation of ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.47 (s, 1H), 8.01 (d, J = 3.1 Hz, 1H), 7.58 (d, J = 3.1 Hz, 1H), 7. 20 (s, 1H), 4.50 (s, 2H), 2.74 (t, J = 7.4 Hz, 2H), 2.58 (s, 3H), 1.67-1.60 (m, 2H), 1.42 (h, J = 7.3 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H). ESI-MS (m / z): 419.1 [M + H] ⁺ .

(E) -3- (4-Methylthiazol-2-yl) -1- (thiazol-2-yl) prop-2-en-1-one was converted to 1- (thiazol-2-yl) -2- ( Prepared from triphenyl-λ5-phosphanylidene) ethane-1-one and 4-methylthiazol-2-carbaldehyde via a Wittig reaction using the synthetic procedure described for the preparation of analog SW209415. ESI-MS (m / z): 237.1 [M + H] ^< +>.

SW217938.2- (Butylsulfinyl) -4- (4-methylthiazol-5-yl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-3-amine is converted to 2-(( (Butylsulfinyl) methyl) thio) -4- (4-methylthiazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile via a cyclization reaction in 12% isolated yield, Prepared using the synthetic procedure described for the preparation of analog SW209415. ¹ H NMR (400 MHz, CD ₃ OD) δ 9.19 (s, 1H), 8.06 (s, 1H), 7.96 (d, J = 3.1 Hz, 1H), 7.78 (d, J = 3.1 Hz, 1 H), 3.40 (ddd, J = 12.7, 9.2, 6.2 Hz, 1 H), 3.14 (ddd, J = 12.7, 9.2, 6.2 Hz) 1H), 2.34 (s, 3H), 1.85-1.58 (m, 2H), 1.60-1.41 (m, 2H), 0.96 (t, J = 7.3 Hz) 3H). ESI-MS (m / z): 435.1 [M + H] ⁺ .

2-(((Butylsulfinyl) methyl) thio) -4- (4-methylthiazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile is converted to 2-(((butylthio) methyl) thio Preparation of analog SW209415 in 96% isolated yield via H ₂ O ₂ oxidation of) -4- (4-methylthiazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile Was prepared using the synthetic procedure described for. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.89 (s, 1H), 8.03 (s, 1H), 7.99 (d, J = 3.1 Hz, 1H), 7.60 (d, J = 3.1 Hz, 1H), 4.69 (d, J = 13.1 Hz, 1H), 4.43 (d, J = 13.1 Hz, 1H), 2.96 (dt, J = 12.9, 8 .1 Hz, 1H), 2.83 (dt, J = 13.0, 7.3 Hz, 1H), 2.53 (s, 3H), 1.83 (p, J = 7.7 Hz, 2H), 1 0.62-1.37 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 435.1 [M + H] ⁺ .

2-(((Butylthio) methyl) thio) -4- (4-methylthiazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile is converted to (E) -3- (4-methylthiazole Analog SW209415 in 58% isolated yield from -5-yl) -1- (thiazol-2-yl) prop-2-en-1-one, 2-cyanoethanethioamide and butyl (chloromethyl) sulfane Prepared using the synthetic procedure described for the preparation of ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.88 (s, 1H), 7.98 (d, J = 3.2 Hz, 1H), 7.96 (s, 1H), 7.58 (d, J = 3.1 Hz, 1H), 4.51 (s, 2H), 2.75 (t, J = 7.5 Hz, 2H), 2.53 (s, 3H), 1.68-1.59 (m, 2H), 1.48-1.36 (m, 2H), 0.91 (t, J = 7.3, 3H). ESI-MS (m / z): 419.1 [M + H] ⁺ .

(E) -3- (4-Methylthiazol-5-yl) -1- (thiazol-2-yl) prop-2-en-1-one was converted to 1- (thiazol-2-yl) -2- ( Prepared from triphenyl-λ5-phosphanylidene) ethane-1-one and 4-methylthiazol-5-carbaldehyde via a Wittig reaction using the synthetic procedure described for the preparation of analog SW209415. ESI-MS (m / z): 237.1 [M + H] ^< +>.

SW217939.2- (Butylsulfinyl) -4- (4-methyloxazol-5-yl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-3-amine is converted to 2-(( 14% isolated yield via cyclization of (butylsulfinyl) methyl) thio) -4- (4-methyloxazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile, Prepared using the synthetic procedure described for the preparation of analog SW209415. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.41 (s, 1H), 8.16 (s, 1H), 7.99 (d, J = 3.2 Hz, 1H), 7.79 (d, J = 3.2 Hz, 1 H), 3.40 (ddd, J = 12.7, 9.3, 6.2 Hz, 1 H), 3.16 (ddd, J = 12.7, 9.3, 6.2 Hz) 1H), 2.33 (s, 3H), 1.89-1.60 (m, 2H), 1.62-1.43 (m, 2H), 0.97 (t, J = 7.3 Hz) 3H). ESI-MS (m / z): 419.1 [M + H] ⁺ .

2-((((Butylsulfinyl) methyl) thio) -4- (4-methyloxazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile is converted to 2-(((butylthio) methyl) thio Preparation of analog SW209415 in 99% isolated yield via H ₂ O ₂ oxidation of) -4- (4-methyloxazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile Was prepared using the synthetic procedure described for. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.16 (s, 1H), 8.05 (s, 1H), 8.02 (d, J = 3.1 Hz, 1H), 7.62 (d, J = 3.1 Hz, 1H), 4.72 (d, J = 13.1 Hz, 1H), 4.40 (d, J = 13.1 Hz, 1H), 2.97 (dt, J = 12.9, 8.2 Hz, 1H), 2.83 (dt, J = 12.9, 7.5 Hz, 1H), 2.54 (s, 3H), 1.84 (p, J = 7.6 Hz, 2H), 1.60-1.39 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). ESI-MS (m / z): 419.1 [M + H] ⁺ .

2-(((Butylthio) methyl) thio) -4- (4-methyloxazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile is converted to (E) -3- (4-methyloxazole Analog SW209415 in 56% isolated yield from -5-yl) -1- (thiazol-2-yl) prop-2-en-1-one, 2-cyanoethanethioamide and butyl (chloromethyl) sulfane Prepared using the synthetic procedure described for the preparation of ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.07 (s, 1H), 8.03 (s, 1H), 8.01 (d, J = 3.1 Hz, 1H), 7.59 (d, J = 3.1 Hz, 1H), 4.51 (s, 2H), 2.76 (t, J = 7.4 Hz, 2H), 2.52 (s, 3H), 1.67-1.60 (m, 2H), 1.49-1.33 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H). ESI-MS (m / z): 403.1 [M + H] +.

(E) -3- (4-Methyloxazol-5-yl) -1- (thiazol-2-yl) prop-2-en-1-one was converted to 1- (thiazol-2-yl) -2- ( Analogue SW209415 from 1.3 equivalents of triphenyl-λ5-phosphanylidene) ethane-1-one and 4-methyloxazole-5-carbaldehyde via Wittig reaction in CH ₃ CN at 90 ° C. for 20 hours. Prepared using the synthetic procedure described for the preparation of ESI-MS (m / z): 221.1 [M + H] ^< +>.

SW2179955.6-((3-methoxypropyl) sulfinyl) -4-phenyl-2- (thiazol-2-yl) thieno [2,3-d] pyrimidin-5-amine. 6-((((3-methoxypropyl) sulfinyl) methyl) thio) -4-phenyl-2- (thiazol-2-yl) -1,6-dihydropyrimidine-5-carbonitrile (0.046 mmol, 20 mg) To a solution of DMF (250 μL) containing KOH (0.023 mmol, 1.3 mg, 0.5 eq .; 2M aqueous solution) was added. The reaction mixture was stirred at room temperature for 10-20 minutes. Upon completion, the reaction was diluted with EtOAc and washed with a 5% aqueous solution of acidic acid. The organic phase was separated and the aqueous layer was extracted twice with EtOAc, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography to give the product in 70% isolated yield. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 8.06 (d, J = 3.1 Hz, 1H), 7.75-7.70 (m, 2H), 7.67-7.62 (m, 3H ), 7.62 (d, J = 3.1 Hz, 1H), 4.84 (s, 2H), 3.50 (t, J = 5.9 Hz, 2H), 3.39-3.28 (m 1H), 3.32 (s, 3H), 3.26-3.16 (m, 1H), 2.10-1.89 (m, 2H). ESI-MS (m / z): 431.1 [M + H] ^< +>.

6-((((3-methoxypropyl) sulfinyl) methyl) thio) -4-phenyl-2- (thiazol-2-yl) -1,6-dihydropyrimidine-5-carbonitrile. Acetic acid (350 μL) and hydrogen peroxide (0.24 mmol, 1.5 eq; 30% aqueous solution) were added 4-((((3-methoxypropyl) thio) methyl) thio) -6-phenyl-2- (thiazole). 2-yl) pyrimidine-5-carbonitrile (0.16 mmol, 68 mg) was added to a solution of chloroform (350 μL). The reaction mixture was stirred at 32 ° C. for 45 minutes. Upon completion, the reaction was diluted with EtOAc, washed with saturated NaHCO ₃ solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 65 mg of the planned product (94%) . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.18-8.09 (m, 3H), 7.68 (d, J = 3.1 Hz, 1H), 7.64-7.51 (m, 3H), 4.77 (d, J = 13.2 Hz, 1H), 4.59 (d, J = 13.3 Hz, 1H), 3.63-3.42 (m, 2H), 3.31 (s, 3H ), 3.26-3.13 (m, 1H), 2.97 (ddd, J = 13.0, 8.0, 6.3 Hz, 1H), 2.19-2.07 (m, 2H) . ESI-MS (m / z): 431.1 [M + H] ^< +>.

4-(((((3-methoxypropyl) thio) methyl) thio) -6-phenyl-2- (thiazol-2-yl) pyrimidine-5-carbonitrile. 4-phenyl-2- (thiazol-2-yl) -6-thioxo-1,6-dihydropyrimidine-5-carbonitrile (0.34 mmol, 100 mg), (chloromethyl) (3-methoxypropyl) sulfane (0 .68 mmol, 104 mg, 2.0 eq) and Et ₃ N (0.87 mmol, 88 mg, 2.5 eq) were refluxed in dry CH ₃ CN (1 mL) for 20 min. The reaction was diluted with EtOAc and water. The organic phase was separated and the aqueous layer was extracted twice with EtOAc. The extracts were combined, washed with saturated NaCl solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was then purified by flash chromatography to give 72 mg of the planned product (52%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.14 (d, J = 3.0 Hz, 1H), 8.13-8.09 (m, 2H), 7.67 (d, J = 3.1 Hz, 1H ), 7.62-7.51 (m, 3H), 4.61 (s, 2H), 3.46 (t, J = 6.3 Hz, 2H), 3.32 (s, 3H), 2. 84 (t, J = 7.2 Hz, 2H), 2.01-1.85 (m, 2H). ESI-MS (m / z): 415.1 [M + H] ⁺ .

4-Phenyl-2- (thiazol-2-yl) -6-thioxo-1,6-dihydropyrimidine-5-carbonitrile was prepared according to the procedure described by Soto ¹ . NaOiPr (1.1 mmol, 1.0 equiv, prepared in situ from sodium and 25 mL dry iPrOH), thiazole-2-carbothioamide (1.1 mmol, 158 mg, 1.0 equiv) and 2- (methoxy (phenyl) A mixture of methylene) malononitrile (1.1 mmol, 202 mg, 1.0 eq) was stirred at room temperature for 5 hours. The reaction was then acidified with conc. HCl, stirred overnight, evaporated and the resulting solid was suspended in acetic acid. The mixture was stirred at 80 ° C. for 2 hours followed by filtration to yield 70% yield of 4-phenyl-2- (thiazol-2-yl) -6-thioxo-1,6-dihydropyrimidine-5-carbonitrile. Obtained at a rate. ESI-MS (m / z): 297.1 [M + H] ^< +>.

SW2179996.6-((2-methoxyethyl) sulfinyl) -4-phenyl-2- (thiazol-2-yl) thieno [2,3-d] pyrimidin-5-amine is converted to 4-(((((2- Synthetic procedure described for the preparation of analog SW217995 in 72% isolated yield from methoxyethyl) sulfinyl) methyl) thio) -6-phenyl-2- (thiazol-2-yl) pyrimidine-5-carbonitrile It was prepared using. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 8.06 (d, J = 3.2 Hz, 1H), 7.78-7.69 (m, 2H), 7.69-7.62 (m, 3H ), 7.62 (d, J = 3.2 Hz, 1H), 4.79 (s, 2H), 3.88-3.80 (m, 1H), 3.72-3.62 (m, 1H) ), 3.62-3.53 (m, 1H), 3.37 (s, 3H), 3.34-3.23 (m, 1H). ESI-MS (m / z): 417.1 [M + H] ^< +>.

4-(((((2-methoxyethyl) sulfinyl) methyl) thio) -6-phenyl-2- (thiazol-2-yl) pyrimidine-5-carbonitrile is converted to 4-(((((2-methoxyethyl)) For the preparation of analog SW217995 in 86% isolated yield via H ₂ O ₂ oxidation of thio) methyl) thio) -6-phenyl-2- (thiazol-2-yl) pyrimidine-5-carbonitrile Prepared using the synthetic procedure described. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.18-8.09 (m, 3H), 7.69 (d, J = 3.1 Hz, 1H), 7.64-7.53 (m, 3H), 4.90 (d, J = 13.2 Hz, 1H), 4.74 (d, J = 13.2 Hz, 1H), 3.99 (ddd, J = 10.4, 6.0, 3.8 Hz, 1H), 3.83 (ddd, J = 11.1, 8.3, 3.4 Hz, 1H), 3.40 (s, 3H), 3.26 (ddd, J = 13.8, 8.2) 3.8 Hz, 1H), 3.14 (ddd, J = 13.7, 6.1, 3.3 Hz, 1H). ESI-MS (m / z): 417.1 [M + H] ^< +>.

4-((((2-methoxyethyl) thio) methyl) thio) -6-phenyl-2- (thiazol-2-yl) pyrimidine-5-carbonitrile was converted to 4-phenyl-2- (thiazol-2- Yl) -6-thioxo-1,6-dihydropyrimidine-5-carbonitrile and (chloromethyl) (2-methoxyethyl) sulfane in 62% isolated yield in a synthesis described for the preparation of analog SW217995 Prepared using the procedure. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.13 (dJ = 3.1 Hz, 1H), 8.12-8.08 (m, 2H), 7.66 (d, J = 3.1 Hz, 1H), 7.61-7.51 (m, 3H), 4.68 (s, 2H), 3.68 (t, J = 6.1 Hz, 2H), 3.37 (s, 3H), 2.93 ( t, J = 6.1 Hz, 2H). ESI-MS (m / z): 401.1 [M + H] ^< +>.

SW2171797.2- (4- (3-Amino-2- (phenylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-4-yl) phenoxy) ethane-1-ol Through the cyclization reaction of 4- (4- (2-hydroxyethoxy) phenyl) -2-(((phenylsulfinyl) methyl) thio) -6- (thiazol-2-yl) nicotinonitrile, 74% Prepared using the synthetic procedure described for the preparation of analog SW209415 in release yield. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 8.02 (s, 1H), 7.91 (d, J = 3.1 Hz, 1H), 7.77-7.69 (m, 2H), 7. 58-7.48 (m, 4H), 7.46-47.42 (m, 2H), 7.13-7.05 (m, 2H), 4.74 (s, 2H), 4.17 ( t, J = 4.4 Hz, 2H), 3.99 (t, J = 4.5 Hz, 2H). ESI-MS (m / z): 494.1 [M + H] ^< +>.

4- (4- (2-hydroxyethoxy) phenyl) -2-(((phenylsulfinyl) methyl) thio) -6- (thiazol-2-yl) nicotinonitrile. Methyl 2- (4- (3-cyano-2-(((phenylsulfinyl) methyl) thio) -6- (thiazol-2-yl) pyridin-4-yl) phenoxy) acetate (60 mg, 0.115 mmol) To a solution of the containing THF (1.4 mL) was added LiBH ₄ (0.23 mmol, 5 mg) and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with EtOAc and water. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the product in 86% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04 (s, 1H), 8.01 (d, J = 3.1 Hz, 1H), 7.85-7.75 (m, 2H), 7.68- 7.58 (m, 3H), 7.50-7.37 (m, 3H), 7.11-7.00 (m, 2H), 4.81 (d, J = 12.9 Hz, 1H), 4.58 (d, J = 12.9 Hz, 1H), 4.16 (t, J = 4.3 Hz, 2H), 4.01 (t, J = 4.5 Hz, 2H). ESI-MS (m / z): 494.1 [M + H] ^< +>.

Methyl 2- (4- (3-cyano-2-(((phenylsulfinyl) methyl) thio) -6- (thiazol-2-yl) pyridin-4-yl) phenoxy) acetate is converted to methyl (E) -2 -(4- (3-oxo-3- (thiazol-2-yl) prop-1-en-1-yl) phenoxy) acetate (patent: WO2015 / 65716A1, 2015), 2-cyanoethanethioamide and (( ^2, 74% isolated yield from chloromethyl) sulfinyl) benzene was prepared using the synthetic procedure described for the preparation of analogs SW209415. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 (s, 1H), 8.00 (d, J = 3.1 Hz, 1H), 7.82-7.75 (m, 2H), 7.68- 7.59 (m, 3H), 7.48-7.41 (m, 3H), 7.12-6.93 (m, 2H), 4.80 (d, J = 12.9 Hz, 1H), 4.71 (s, 2H), 4.60 (d, J = 12.9 Hz, 1H), 3.83 (s, 3H). ESI-MS (m / z): 522.1 [M + H] ^< +>.

SW2179.98.2- (Butylsulfinyl) -4- (4- (2-fluoroethoxy) phenyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-3-amine is converted to 2- ( 14% isolated yield via cyclization of ((butylsulfinyl) methyl) thio) -4- (4- (2-fluoroethoxy) phenyl) -6- (thiazol-2-yl) nicotinonitrile And prepared using the synthetic procedure described for the preparation of analog SW209415. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 8.06 (s, 1H), 7.93 (d, J = 3.2, 1H), 7.55 (d, J = 3.3 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 9.0 Hz, 2H), 4.81 (dm, J = 48 Hz, 2H), 4.66 (s, 2H) ), 4.31 (dm, J = 28 Hz, 2H), 3.37-3.20 (m, 1H), 3.11 (ddd, J = 12.8, 9.2, 6.5 Hz, 1H) 1.81-1.67 (m, 2H), 1.57-1.38 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 476.1 [M + H] ⁺ .

2-((((Butylsulfinyl) methyl) thio) -4- (4- (2-fluoroethoxy) phenyl) -6- (thiazol-2-yl) nicotinonitrile is converted to 2-(((butylthio) methyl) Analog SW209415 in 97% isolated yield via H ₂ O ₂ oxidation of thio) -4- (4- (2-fluoroethoxy) phenyl) -6- (thiazol-2-yl) nicotinonitrile. Prepared using the synthetic procedure described for the preparation of ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.09 (s, 1H), 8.00 (d, J = 3.1 Hz, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7. 60 (d, J = 3.1 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 4.84 (dm, J = 48.1 Hz, 2H), 4.75 (d, J = 13.1 Hz, 1H), 4.40 (d, J = 13.1 Hz, 1H), 4.31 (dm, J = 28.1 Hz, 2H), 2.98 (dt, J = 13.0, 8.2 Hz, 1H), 2.83 (dt, J = 12.9, 7.3 Hz, 1H), 1.93-1.74 (m, 2H), 1.63-1.38 (m, 2H) ), 0.96 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 476.1 [M + H] ⁺ .

2-(((Butylthio) methyl) thio) -4- (4- (2-fluoroethoxy) phenyl) -6- (thiazol-2-yl) nicotinonitrile. 2-((((Butylthio) methyl) thio) -4- (4- (2-hydroxyethoxy) phenyl) -6- (thiazol-2-yl) nicotinonitrile (Patent: WO2015 / 65716A1, 2015) (30 mg , 0.065 mmol) to a solution of 5 ml methylene chloride was added morpholinosulfur trifluoride (23 mg, 0.13 mmol, 2.0 equiv) and the reaction was monitored by LC / MS. The reaction mixture was diluted with methylene chloride and a saturated solution of sodium bicarbonate was added. The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the product in 56% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.01 (s, 1H), 7.98 (d, J = 3.1 Hz, 1H), 7.68-7.62 (m, 2H), 7.56 ( d, J = 3.1 Hz, 1H), 7.10-7.03 (m, 2H), 4.79 (dm, J = 47, 2H), 4.52 (s, 2H), 4.28 ( dm, J = 27 Hz, 2H), 2.75 (t, J = 7.6 Hz, 2H), 1.72-1.52 (m, 2H), 1.50-1.36 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H). ESI-MS (m / z): 460.1 [M + H] ^< +>.

SW217999.4- (2- (4- (3-Amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-4-yl) phenoxy) ethoxy)- 4-oxobutanoic acid. 2- (4- (3-Amino-2- (butylsulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-4-yl) phenoxy) ethane-1-ol (patent: To a solution of methylene chloride containing WO2015 / 65716A1, 2015) (13 mg, 0.027 mmol), Et ₃ N (82 mg, 0.81 mmol, 3.0 eq), succinic anhydride (5.5 mg, 0.054 mmol, 2.0 equivalents) and a catalytic amount of DMAP was added. The reaction was monitored by LC / MS. The reaction mixture was diluted with methylene chloride and a saturated solution of sodium bicarbonate was added. The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by PTLC. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 8.02 (s, 1H), 7.89 (d, J = 3.1 Hz, 1H), 7.52 (d, J = 3.2 Hz, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 4.72 (s, 2H), 4.47 (t, J = 5.3 Hz) 2H), 4.31 (t, J = 5.0 Hz, 2H), 3.35-3.21 (m, 1H), 3.20-3.04 (m, 1H), 2.75-2 .49 (m, 4H), 1.82-1.56 (m, 2H), 1.56-1.38 (m, 2H), 0.93 (t, J = 7.3 Hz, 4H). ESI-MS (m / z): 574.1 [M + H] ⁺ .

SW2108030. N- (2- (butylsulfinyl) -4-phenyl-6- (thiophen-2-yl) thieno [2,3-b] pyridin-3-yl) acetamide. Acetic acid (20 μL) and hydrogen peroxide (0.18 mmol, 2.0 eq; 30% aqueous solution) were added to N- (2- (butylthio) -4-phenyl-6- (thiophen-2-yl) thieno [2, 3-b] Pyridin-3-yl) acetamide (0.092 mmol, 4 mg) was added to a solution of chloroform (20 μL). The reaction mixture was stirred at 32 ° C. for 45 minutes. Upon completion, the reaction was diluted with EtOAc, washed with saturated NaHCO ₃ solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 4 mg of the planned product. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 7.67 (dd, J = 3.8, 1.2 Hz, 1H), 7.59-7.56 (m, 4H), 7.48 (dd, J = 5.0, 1.1 Hz, 2H), 7.13 (dd, J = 5.0, 3.7 Hz, 1H), 7.41 (s, 1H), 6.94 (s, 1H), 3 .39-3.24 (m, 1H), 3.20-3.02 (m, 1H), 1.88-1.75 (m, 2H), 1.55 (s, 3H), 1.57 -1.43 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 455.1 [M + H] ⁺ .

N- (2- (butylthio) -4-phenyl-6- (thiophen-2-yl) thieno [2,3-b] pyridin-3-yl) acetamide. To a solution of 2- (butylthio) -4-phenyl-6- (thiophen-2-yl) thieno [2,3-b] pyridin-3-amine (0.023 mmol, 9 mg) in THF was added pyridine (0. 068 mmol, 5.4 mg, 3.0 eq), catalytic amounts of DMAP and acetyl chloride (0.046 mmol, 3.6 mg) were added. The reaction mixture was stirred at room temperature for 15 minutes. Upon completion, the reaction was diluted with EtOAc, washed with saturated NaHCO ₃ solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the planned product. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64-7.60 (m, 1H), 7.52-7.45 (m, 4H), 7.44-7.36 (m, 3H), 7. 13-7.06 (m, 1H), 6.27 (s, 1H), 2.96 (t, J = 7.4 Hz, 2H), 1.66 (p, J = 7.7 Hz, 2H), 1.55 (s, 3H), 1.43 (h, J = 7.3 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H). ESI-MS (m / z): 439.1 [M + H] ⁺ .

2- (Butylthio) -4-phenyl-6- (thiophen-2-yl) thieno [2,3-b] pyridin-3-amine. A flask containing Zn dust (63 mg, 0.97 mmol, 8.0 equiv) was purged with nitrogen for 10 minutes. Dry THF (6 mL) was added 10 times and the gray suspension was cooled to 0 ° C. and TiCl ₄ (0.48 mmol, 91 mg, 4.0 eq) was added. After stirring at 0 ° C. for 10 minutes, 2- (butylsulfinyl) -4-phenyl-6- (thiophen-2-yl) thieno [2,3-b] pyridin-3-amine (Patent: WO2013 / 158649A1, 2013) (50 mg, 0.12 mmol) containing 2 mL dry THF was added and the reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with 5 mL 3N NaOH and 5 mL water. The aqueous layer was extracted with EtOAc. The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 7.63 (dd, J = 3.7, 1.2 Hz, 1H), 7.57-7.50 (m, 3H), 7.50-7.46 (M, 2H), 7.43 (s, 1H), 7.41 (dd, J = 5.0, 1.1 Hz, 1H), 7.10 (dd, J = 5.0, 3.7 Hz, 1H) 3.98 (s, 2H), 2.76 (t, J = 7.3 Hz, 2H), 1.66-1.57 (m, 2H), 1.42 (h, J = 7.3 Hz) 2H), 0.90 (t, J = 7.4 Hz, 3H). ESI-MS (m / z): 397.1 [M + H] ^< +>.

SW218031. Methyl (2- (butylsulfinyl) -4-phenyl-6- (thiophen-2-yl) thieno [2,3-b] pyridin-3-yl) carbamate is converted to methyl (2- (butylthio) -4-phenyl Prepared using the synthetic procedure described for the preparation of analog SW218030 via H ₂ O ₂ oxidation of -6- (thiophen-2-yl) thieno [2,3-b] pyridin-3-yl) carbamate did. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 7.71 (dd, J = 3.8, 1.2 Hz, 1H), 7.61 (s, 1H), 7.57-7.34 (m, 6H) ), 7.15 (dd, J = 5.0, 3.8 Hz, 1H), 6.15 (s, 1H), 3.48 (s, 3H), 3.27-3.18 (m, 1H) ), 3.18-3.10 (m, 1H), 1.73-1.60 (m, 2H), 1.53-1.33 (m, 2H), 0.97 (t, J = 7) .3Hz, 3H). ESI-MS (m / z): 471.1 [M + H] ^< +>.

Methyl (2- (butylthio) -4-phenyl-6- (thiophen-2-yl) thieno [2,3-b] pyridin-3-yl) carbamate. To a solution of 2- (butylthio) -4-phenyl-6- (thiophen-2-yl) thieno [2,3-b] pyridin-3-amine (0.063 mmol, 25 mg) in methylene chloride was added Et ₃ N. (0.189 mmol, 19 mg, 3.0 eq) and methyl chloroformate (0.075 mmol, 7 mg, 1.2 eq) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was diluted with methylene chloride, washed with saturated NaHCO ₃ solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to give 8 mg of the planned product. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.63 (dd, J = 3.7, 1.2 Hz, 1H), 7.51 (s, 1H), 7.49-7.43 (m, 3H), 7.43-7.35 (m, 3H), 7.11 (dd, J = 5.1, 3.7 Hz, 1H), 5.71 (s, 1H), 3.39 (s, 3H), 2.96 (t, J = 7.3 Hz, 2H), 1.77-1.59 (m, 2H), 1.42 (h, J = 7.3 Hz, 2H), 0.90 (t, J = 7.4 Hz, 3H). ESI-MS (m / z): 455.1 [M + H] ⁺ .

SW218313. (3-Amino-4-phenyl-6- (thiophen-2-yl) thieno [2,3-b] pyridin-2-yl) (piperidin-1-yl) methanone. A solution of DMF containing 2-((2-oxo-2- (piperidin-1-yl) ethyl) thio) -4-phenyl-6- (thiophen-2-yl) nicotinonitrile (20 mg, 0.048 mmol) To was added ^t BuOK (0.072 mmol, 8.0 mg, 1.5 eq) and the reaction mixture was stirred at 100 ° C. Upon completion, the reaction was diluted with EtOAc, washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the planned product in 95% yield. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 7.69 (dd, J = 3.7, 1.2 Hz, 1H), 7.60-7.46 (m, 7H), 7.19-7.10. (M, 1H), 5.11 (s, 2H), 3.74-3.56 (m, 4H), 1.80-1.51 (m, 6H). ESI-MS (m / z): 420.1 [M + H] ^< +>.

2-((2-oxo-2- (piperidin-1-yl) ethyl) thio) -4-phenyl-6- (thiophen-2-yl) nicotinonitrile. EtOH solution containing 4-phenyl-6- (thiophen-2-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile (Patent: WO2013 / 158649A1, 2013) (50 mg, 0.17 mmol) To was added NaOEt (23 mg, 0.34 mmol. 2.0 equiv) and 2-chloro-1- (piperidin-1-yl) ethan-1-one (55 mg, 0.34 mmol, 2.0 equiv). The reaction mixture was stirred at 60 ° C. for 2 hours. Upon completion, the reaction was evaporated, diluted with EtOAc, washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to give the planned product in 72% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.68 (dd, J = 3.8, 1.1 Hz, 1H), 7.63-7.56 (m, 2H), 7.55-7.47 (m 4H), 7.39 (s, 1H), 7.14 (dd, J = 5.0, 3.8 Hz, 1H), 4.06 (s, 2H), 3.67-3.56 (m) 4H), 1.75-1.61 (m, 6H). ESI-MS (m / z): 420.1 [M + H] ^< +>.

SW218383.3-Amino-4-phenyl-N-propyl-6- (thiophen-2-yl) thieno [2,3-b] pyridine-2-sulfonamide. Solution of DMF containing 4-phenyl-6- (thiophen-2-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile (Patent: WO2013 / 158649A1, 2013) (30 mg, 0.1 mmol) To was added 1-chloro-N-propylmethanesulfonamide (34 mg, 0.2 mmol, 2.0 eq) and Et ₃ N (30 mg, 0.3 mmol, 3.0 eq) and the reaction mixture was added at 100 ° C. at 100 ° C. Stir overnight. Upon completion, the reaction was diluted with EtOAc, washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to give the planned product in 91% yield. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 7.79 (d, J = 3.8 Hz, 1H), 7.72-7.53 (m, 7H), 7.32-7.13 (m, 1H ), 5.06 (s, 2H), 4.59 (t, J = 6.3 Hz, 1H), 1.47 (h, J = 7.3 Hz, 2H), 1.34-1.20 (m) 2H), 0.83 (t, J = 7.4 Hz, 3H). ESI-MS (m / z): 430.1 [M + H] ^< +>.

SW218398.4- (1,2-dimethyl-1H-imidazol-5-yl) -2-((ethoxymethyl) sulfinyl) -6- (thiazol-2-yl) thieno [2,3-b] pyridine-3 The amine to 4- (1,2-dimethyl-1H-imidazol-5-yl) -2-((((ethoxymethyl) sulfinyl) methyl) thio) -6- (thiazol-2-yl) nicotinonitrile Was prepared using the synthetic procedure described for the preparation of analog SW209415 in 68% isolated yield. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.05 (s, 1H), 7.98 (d, J = 3.2, 1H), 7.79 (d, J = 3.2, 1H), 7 .15 (s, 1H), 4.92 (d, J = 10.4 Hz, 1H), 4.81 (d, J = 10.3 Hz, 1H), 4.06-3.74 (m, 2H) 3.46 (s, 3H), 2.49 (s, 3H), 1.25 (t, J = 7.0, 3H). ESI-MS (m / z): 434.1 [M + H] ⁺ .

4- (1,2-dimethyl-1H-imidazol-5-yl) -2-((((ethoxymethyl) sulfinyl) methyl) thio) -6- (thiazol-2-yl) nicotinonitrile H ₂ O ₂ oxidation of (1,2-dimethyl-1H-imidazol-5-yl) -2-((((ethoxymethyl) thio) methyl) thio) -6- (thiazol-2-yl) nicotinonitrile Via the synthetic procedure described for the preparation of analog SW209415 in 87% isolated yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.00 (d, J = 3.1 Hz, 1H), 7.96 (s, 1H), 7.61 (d, J = 3.1 Hz, 1H), 7. 44 (s, 1H), 4.77-4.63 (m, 4H), 4.03 (dq, J = 9.5, 7.1 Hz, 1H), 3.88 (dq, J = 9.5) 7.0 Hz, 1H), 3.65 (s, 3H), 2.52 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H). ESI-MS (m / z): 434.1 [M + H] ⁺ .

4- (1,2-Dimethyl-1H-imidazol-5-yl) -2-((((ethoxymethyl) thio) methyl) thio) -6- (thiazol-2-yl) nicotinonitrile is ) -3- (1,2-dimethyl-1H-imidazol-5-yl) -1- (thiazol-2-yl) prop-2-en-1-one, 2-cyanoethanethioamide and (chloromethyl) ( Prepared from ethoxymethyl) sulfane (3.5 eq) in 16% isolated yield using the synthetic procedure described for the preparation of analog SW209415. ¹ H NMR (400 MHz, chloroform-d) δ 7.9 (d, J = 3.1 Hz, 1H), 7.89 (s, 1H), 7.58 (d, J = 3.1 Hz, 1H), 7 .40 (s, 1H), 4.84 (s, 2H), 4.55 (s, 2H), 3.70-3.64 (m, 2H), 3.63 (s, 3H), 2. 51 (s, 3H), 1.26 (t, J = 7.0 Hz, 3H). ESI-MS (m / z): 418.1 [M + H] ^< +>.

(Chloromethyl) (ethoxymethyl) sulfane. To a solution of 2 mL EtOH containing bis (chloromethyl) sulfane (100 mg, 0.76 mmol) was added EtONa (52 mg, 0.76 mmol) and the reaction mixture was stirred overnight at room temperature. The product was used as EtOH solution without further purification.

SW218199.2- (Butylsulfinyl) -4-phenyl-6- (thiophen-2-yl) thieno [2,3-b] pyridin-3-ol. To a solution of DMF (200 μL) containing ethyl 2-(((butylsulfinyl) methyl) thio) -4-phenyl-6- (thiophen-2-yl) nicotinate (16 mg, 0.035 mmol) was added ^t BuOK under nitrogen. (4 mg, 0.035 mmol) was added. The reaction mixture was stirred for several minutes at room temperature (the reaction was followed by LC / MS and TLC). Upon completion, the reaction was diluted with EtOAc and water. The organic phase was separated and the aqueous layer was extracted twice with EtOAc. The extracts were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give 6 mg of the planned product. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.00-7.89 (m, 1H), 7.72 (d, J = 3.0, 1H), 7.64-7.39 (m, 6H) , 7.23-7.15 (m, 1H), 3.29-3.22 (m, 1H), 3.18-3.06 (m, 1H), 1.89-1.60 (m, 2H), 1.61-1.42 (m, 2H), 1.09-0.89 (t, J = 7.4 Hz, 3H). ESI-MS (m / z): 414.1 [M + H] ⁺ .

Ethyl 2-((((butylsulfinyl) methyl) thio) -4-phenyl-6- (thiophen-2-yl) nicotinate is converted to 2-(((butylthio) methyl) thio) -4-phenyl-6- (thiophene). Prepared using the synthetic procedure described for the preparation of analog SW209415 in 67% isolated yield via H ₂ O ₂ oxidation of -2-yl) nicotinate. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.69 (dd, J = 3.8, 1.2 Hz, 1 H), 7.48 (dd, J = 5.0, 1.1 Hz, 1 H), 7.46 −7.39 (m, 4H), 7.39−7.32 (m, 2H), 7.14 (dd, J = 5.0, 3.7 Hz, 1H), 4.74 (d, J = 13.0 Hz, 1H), 4.36 (d, J = 13.0 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H), 2.99 (dt, J = 13.0, 8 .1 Hz, 1H), 2.89-2.67 (m, 1H), 1.83 (p, J = 7.6 Hz, 2H), 1.60-1.36 (m, 2H), 0.94 (T, J = 7.2 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H). ESI-MS (m / z): 460.1 [M + H] ^< +>.

Ethyl 2-(((butylthio) methyl) thio) -4-phenyl-6- (thiophen-2-yl) nicotinate. To a suspension of 2 mL CH ₃ CN containing ethyl 4-phenyl-6- (thiophen-2-yl) -2-thioxo-1,2-dihydropyridine-3-carboxylate (52 mg, 0.15 mmol) was added Et. ₃ N (45 mg, 0.45 mmol, 3.0 eq), and was added butyl (chloromethyl) sulfane (0.23 mmol, 32 mg). The reaction mixture was stirred at 80 ° C. for 20 minutes. Upon completion, the reaction was diluted with EtOAc and water. The organic phase was separated and the aqueous layer was extracted twice with EtOAc. The extracts were combined, washed with saturated NaCl solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give the planned product (50%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (dt, J = 3.7, 0.9 Hz, 1H), 7.48-7.39 (m, 4H), 7.40-7.34 (m 3H), 7.12 (ddd, J = 5.0, 3.7, 0.7 Hz, 1H), 4.49 (s, 2H), 4.09 (q, J = 7.1 Hz, 2H) 2.73 (t, J = 7.5 Hz, 2H), 1.71-1.59 (m, 2H), 1.41 (h, J = 7.4 Hz, 2H), 0.95 (t, J = 7.1 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H). ESI-MS (m / z): 444.1 [M + H] ^< +>.

Ethyl 4-phenyl-6- (thiophen-2-yl) -2-thioxo-1,2-dihydropyridine-3-carboxylate. Sodium sulfide (36 mg, 0.46 mmol, 2.0 eq) was added to a solution of DMF (300 μL) containing ethyl 2-bromo-4-phenyl-6- (thiophen-2-yl) nicotinate (90 mg, 0.23 mmol). And the reaction mixture was stirred at 50 ° C. Upon completion, the reaction was diluted with EtOAc, washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography to give the product in 62% yield. ESI-MS (m / z): 342.1 [M + H] ^< +>.

2-Bromo-4-phenyl-6- (thiophen-2-yl) nicotinate in 51% yield of ethyl 2-cyano-4-oxo-2-phenyl-4- (thiophen-2-yl) butanoate Prepared according to the procedure reported by Girgis ³ via a cyclization reaction with bromine. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.67 (d, J = 3.7 Hz, 1H), 7.55 (s, 1H), 7.51-7.35 (m, 5H), 7.15- 7.10 (m, 1H), 7.07 (d, J = 5.1 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 1.10 (t, J = 7.1 Hz) 3H).

SW218400.4-Phenyl-2- (piperidin-1-ylsulfonyl) -6- (thiophen-2-yl) thieno [2,3-b] pyridin-3-amine. To a solution of DMF containing 1-((chloromethyl) sulfonyl) piperidine (98 mg, 0.5 mmol) was added LiBr (650 mg, 7.5 mmol, 15 eq) and the reaction mixture was stirred at 100 ° C. overnight. Thereafter, 4-phenyl-6- (thiophen-2-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile (Patent: WO2013 / 158649A1, 2013) (73.5 mg, 0.25 mmol), Subsequently Et ₃ N (126 mg, 1.25 mmol) was added and the reaction mixture was stirred at 100 ° C. for 20 h. After cooling to room temperature, the reaction was diluted with EtOAc, washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to give the planned product in 25% yield. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 7.72 (dd, J = 3.7, 1.1 Hz, 1H), 7.61-7.55 (m, 3H), 7.54 (s, 1H ), 7.62-7.53 (m, 3H), 7.16 (dd, J = 5.0, 3.7 Hz, 1H), 4.98 (s, 2H), 3.17 (t, J = 5.6 Hz, 4H), 1.72-1.59 (m, 4H), 1.54-1.39 (m, 2H). ESI-MS (m / z): 456.1 [M + H] ⁺ .

SW218875.2- (butylsulfinyl) -4- (1,4-dimethyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-3-amine Through the cyclization of 2-(((butylsulfinyl) methyl) thio) -4- (1,4-dimethyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile Was prepared using the synthetic procedure described for the preparation of analog SW209415 in 69% isolated yield. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) 1: 1 rotamer ratio: δ 8.07 (d, J = 1.3 Hz, 1H), 8.00-7.91 (m, 1H), 7.60 -7.53 (m, 2H), 4.68 (s, 1H, one rotamer), 4.61 (s, 1H, one rotamer), 3.47 (s, 1.5H, One rotamer), 3.44 (s, 1.5H, one rotamer), 3.32-3.21 (m, 1H), 3.19-3.02 (m, 1H), 2.16 (s, 1.5H, one rotamer), 2.14 (s, 1.5H, one rotamer), 1.80-1.64 (m, 2H), 1.57 -1.43 (m, 2H), 0.95 (t, J = 7.3 Hz, 1.5H, one rotamer), 0.95 (t, J = 7.3 Hz, 1.5H, 1 Rotational isomerism ) ESI-MS (m / z ): 432.1 [M + H] +.

2-(((Butylsulfinyl) methyl) thio) -4- (1,4-dimethyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile is converted to 2-((( 95% simple via H ₂ O ₂ oxidation of butylthio) methyl) thio) -4- (1,4-dimethyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile Prepared using the synthetic procedure described for the preparation of analog SW209415 in release yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.00 (d, J = 3.2 Hz, 1H), 7.93 (s, 1H), 7.68 (s, 1H), 7.62 (d, J = 3.1 Hz, 1H), 4.73 (m, 1H), 4.47 (m, 1H), 3.64 (s, 3H), 2.99 (dt, J = 13.0, 8.2 Hz, 1H), 2.88 (dt, J = 13.0, 7.0 Hz, 1H), 2.27 (s, 3H), 1.85 (p, J = 7.7 Hz, 2H), 1.65 1.40 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 432.1 [M + H] ^< +>.

2-(((Butylthio) methyl) thio) -4- (1,4-dimethyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile is converted to (E) -3- From (1,4-dimethyl-1H-imidazol-5-yl) -1- (thiazol-2-yl) prop-2-en-1-one, 2-cyanoethanethioamide and butyl (chloromethyl) sulfane, 99 Prepared using the synthetic procedure described for the preparation of analog SW209415 in% isolated yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (d, J = 3.1 Hz, 1 H), 7.85 (s, 1 H), 7.59 (d, J = 3.1 Hz, 1 H), 7. 55 (s, 1H), 4.52 (d, J = 3.2 Hz, 2H), 3.62 (s, 3H), 2.77 (t, J = 7.3 Hz, 2H), 2.27 ( s, 3H), 1.77-1.56 (m, 2H), 1.56-1.33 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 416.1 [M + H] ⁺ .

(E) -3- (1,4-Dimethyl-1H-imidazol-5-yl) -1- (thiazol-2-yl) prop-2-en-1-one is substituted with 1- (4-methylthiazol- 2-yl) -2- (triphenyl-λ5-phosphanylidene) ethane-1-one and 1,4-dimethyl-1H-imidazole-5-carbaldehyde via Wittig (5 days) reaction, 50% simple Prepared using the synthetic procedure described for the preparation of analog SW209415 in release yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.00 (d, J = 3.0 Hz, 1 H), 7.92 (d, J = 16.1 Hz, 1 H), 7.66 (d, J = 3.0 Hz) 1H), 7.60 (d, J = 16.0 Hz, 1H), 7.47 (s, 1H), 3.78 (s, 3H), 2.48 (s, 3H). ESI-MS (m / z): 234.1 [M + H] ^< +>.

1,4-dimethyl-1H-imidazole-5-carbaldehyde and 1,5-dimethyl-1H-imidazole-4-carbaldehyde. 4-methyl -1H- imidazole-5-carbaldehyde (1.0 g, 9 mmol) and, MeI (1.3g, 9mmol, 1.0 _{eq), K 2 CO 3 (2.5g} , 19mmol) CH 3 including Combined with 15 mL CN and stirred overnight at reflux. After cooling to room temperature, the inorganic solids are removed by filtration, the solvent is removed, the residue is purified by column chromatography, 1,4-dimethyl-1H-imidazole-5-carbaldehyde and 1,5-dimethyl- 1H-imidazole-4-carbaldehyde was obtained as a separated fraction.

1,4-Dimethyl-1H-imidazole-5-carbaldehyde. < ¹ > H NMR (400 MHz, CDCl3) [delta] 9.81 (s, 1H), 7.47 (s, 1H), 3.86 (s, 3H), 2.47 (s, 3H). ESI-MS (m / z): 125.1 [M + H] ^< +>.

1,5-dimethyl-1H-imidazole-4-carbaldehyde. ¹ H NMR (400 MHz, CD3OD) δ 9.78 (s, 1H), 7.75 (s, 1H), 3.69 (s, 3H), 2.54 (s, 3H). ESI-MS (m / z): 125.1 [M + H] ^< +>.

SW218847.2- (Butylsulfinyl) -4- (2-ethyl-1-methyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) thieno [2,3-b] pyridine-3- The amine is converted into a 2-(((butylsulfinyl) methyl) thio) -4- (2-ethyl-1-methyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile ring. Prepared using the synthetic procedure described for the preparation of analog SW209415 in 66% isolated yield via the isomerization reaction. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 8.08 (s, 1H), 7.95 (d, J = 3.2 Hz, 1H), 7.56 (d, J = 3.2 Hz, 1H), 7.12 (s, 1H), 4.74 (s, 2H), 3.40 (s, 3H), 3.26 (ddd, J = 12.8, 8.9, 6.3 Hz, 1H), 3.11 (ddd, J = 12.8, 8.9, 6.7 Hz, 1H), 2.78 (q, J = 7.5 Hz, 2H), 1.85-1.61 (m, 2H) 1.61-1.41 (m, 2H), 1.38 (t, J = 7.5 Hz, 3H), 0.96 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 446.1 [M + H] ⁺ .

2-(((Butylsulfinyl) methyl) thio) -4- (2-ethyl-1-methyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile is converted to 2- ( Via H ₂ O ₂ oxidation of ((butylthio) methyl) thio) -4- (2-ethyl-1-methyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile , 94% isolated yield, using the synthetic procedure described for the preparation of analog SW209415. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (d, J = 3.1 Hz, 1H), 7.94 (s, 1H), 7.59 (d, J = 3.1 Hz, 1H), 7. 45 (s, 1H), 4.70 (d, J = 13.1 Hz, 1H), 4.40 (d, J = 13.1 Hz, 1H), 3.63 (s, 3H), 2.96 ( dt, J = 12.9, 8.1 Hz, 1H), 2.90-2.69 (m, 3H), 1.93-1.72 (m, 2H), 1.59-1.43 (m 2H), 1.39 (t, J = 7.5 Hz, 3H), 0.94 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 446.1 [M + H] ⁺ .

2-((((Butylthio) methyl) thio) -4- (2-ethyl-1-methyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile is converted to (E)- 3- (2-Ethyl-1-methyl-1H-imidazol-5-yl) -1- (thiazol-2-yl) prop-2-en-1-one, 2-cyanoethanethioamide and butyl (chloromethyl) Prepared from sulfane in 66% isolated yield using the synthetic procedure described for the preparation of analog SW209415. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (d, J = 3.1, 1H), 7.87 (s, 1H), 7.57 (d, J = 3.2 Hz, 1H), 7. 41 (s, 1H), 4.50 (s, 2H), 3.62 (s, 3H), 2.78 (q, J = 7.6 Hz, 2H), 2.75 (t, J = 7. 3Hz, 2H), 1.71-1.53 (m, 2H), 1.49-1.31 (m, 2H), 1.39 (t, J = 7.5 Hz, 3H) 0.91 (t J = 7.4 Hz, 3H). ESI-MS (m / z): 430.1 [M + H] ^< +>.

(E) -3- (2-Ethyl-1-methyl-1H-imidazol-5-yl) -1- (thiazol-2-yl) prop-2-en-1-one was converted to 1- (4-methyl From thiazol-2-yl) -2- (triphenyl-λ5-phosphanylidene) ethane-1-one and 2-ethyl-1-methyl-1H-imidazole-5-carbaldehyde via Wittig (4 days) reaction , 58% isolated yield, using the synthetic procedure described for the preparation of analog SW209415. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.01 (d, J = 3.0 Hz, 1 H), 7.82 (d, J = 15.8 Hz, 1 H), 7.70 (d, J = 15.8 Hz) 1H), 7.66 (d, J = 3.0 Hz, 1H), 7.64 (s, 1H), 3.65 (s, 3H), 2.73 (q, J = 7.5 Hz, 2H) ), 1.33 (t, J = 7.5 Hz, 3H). ESI-MS (m / z): 248.1 [M + H] ^< +>.

2-Ethyl-1-methyl-1H-imidazole-5-carbaldehyde. To a solution of Et ₂ O (30 mL) containing 2-ethyl-1-methyl-1H-imidazole (1.36 g, 12.36 mmol) was added n-BuLi (12.50 mmol, 5 mL of 2.5 M hexane solution) at room temperature. Added at. The reaction mixture was stirred at room temperature for 3 hours and 2.2 mL of DMF was then added. The reaction mixture was stirred overnight at room temperature, quenched with NH ₄ Cl, extracted with DCM, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to give the planned product in 64% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.62 (s, 1H) 7.66 (s, 1H), 3.84 (s, 3H), 2.71 (q, J = 7.6 Hz, 2H), 1.33 (t, J = 7.6 Hz, 3H). ESI-MS (m / z): 139.1 [M + H] ^< +>.

SW218847.2- (butylsulfinyl) -4- (1,5-dimethyl-1H-imidazol-4-yl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-3-amine Through the cyclization reaction of 2-(((butylsulfinyl) methyl) thio) -4- (1,5-dimethyl-1H-imidazol-4-yl) -6- (thiazol-2-yl) nicotinonitrile Prepared using the synthetic procedure described for the preparation of analog SW209415 in 87% isolated yield. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 8.06 (s, 1H), 7.94 (d, J = 3.2 Hz, 1H), 7.60 (s, 1H), 7.54 (d, J = 3.1 Hz, 1H), 6.43 (s, 2H), 3.67 (s, 3H), 3.25 (ddd, J = 12.7, 9.3, 5.8 Hz, 1H), 3.09 (ddd, J = 12.7, 9.4, 6.2 Hz, 1H), 2.45 (s, 3H), 1.77-1.60 (m, 2H), 1.58-1 .39 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 432.1 [M + H] ^< +>.

2-(((Butylsulfinyl) methyl) thio) -4- (1,5-dimethyl-1H-imidazol-4-yl) -6- (thiazol-2-yl) nicotinonitrile is converted to 2-((( 96% simple via H ₂ O ₂ oxidation of butylthio) methyl) thio) -4- (1,5-dimethyl-1H-imidazol-4-yl) -6- (thiazol-2-yl) nicotinonitrile Prepared using the synthetic procedure described for the preparation of analog SW209415 in release yield. _{^{1 H NMR (400MHz, CDCl 3}} ) δ8.12 (s, 1H), 7.95 (d, J = 3.1Hz, 1H), 7.56 (s, 1H), 7.54 (d, J = 3.1 Hz, 1H), 4.74 (d, J = 13.0 Hz, 1H), 4.36 (d, J = 13.0 Hz, 1H), 3.63 (s, 3H), 2.96 ( dt, J = 12.9, 8.2 Hz, 1H), 2.79 (dt, J = 12.9, 7.3 Hz, 1H), 2.41 (s, 3H), 1.89-1.72. (M, 2H), 1.63-1.37 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 432.1 [M + H] ^< +>.

2-(((Butylthio) methyl) thio) -4- (1,5-dimethyl-1H-imidazol-4-yl) -6- (thiazol-2-yl) nicotinonitrile is converted to (E) -3- From (1,5-dimethyl-1H-imidazol-4-yl) -1- (thiazol-2-yl) prop-2-en-1-one, 2-cyanoethanethioamide and butyl (chloromethyl) sulfane, 64 Prepared using the synthetic procedure described for the preparation of analog SW209415 in% isolated yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.05 (s, 1H), 7.94 (d, J = 3.2 Hz, 1H), 7.55 (s, 1H), 7.52 (d, J = 3.2 Hz, 1H), 4.50 (s, 2H), 3.62 (s, 3H), 2.74 (t, J = 7.2 Hz, 2H), 2.39 (s, 3H), 1 .72-1.55 (m, 2H), 1.41 (h, J = 7.4 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 416.1 [M + H] ⁺ .

(E) -3- (1,5-Dimethyl-1H-imidazol-4-yl) -1- (thiazol-2-yl) prop-2-en-1-one is substituted with 1- (4-methylthiazol- 2-yl) -2- (triphenyl-λ5-phosphanylidene) ethane-1-one and 1,5-dimethyl-1H-imidazole-4-carbaldehyde (4-methyl-1H-imidazole-5-carbaldehyde- Prepared from the two-region isomer alkylation reaction) via the Wittig (5 day) reaction in 43% isolated yield using the synthetic procedure described for the preparation of analog SW209415. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.01 (d, J = 3.0 Hz, 1 H), 8.00 (d, J = 15.3 Hz, 1 H), 7.94 (d, J = 15.3 Hz) 1H), 7.63 (d, J = 3.0 Hz, 1H), 7.48 (s, 1H), 3.58 (s, 3H), 2.37 (s, 3H). ESI-MS (m / z): 234.1 [M + H] ^< +>.

SW218847.2- (butylsulfinyl) -4- (1-cyclopropyl-2-methyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) thieno [2,3-b] pyridine-3 The amine to 2-(((butylsulfinyl) methyl) thio) -4- (1-cyclopropyl-2-methyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile Was prepared using the synthetic procedure described for the preparation of analog SW209415 in 73% isolated yield. 1H NMR (400 MHz, CD ₂ Cl ₂ ) δ 8.13 (s, 1H), 7.94 (d, J = 3.1 Hz, 1H), 7.56 (d, J = 3.2 Hz, 1H), 7 .03 (s, 1H), 4.83 (s, 2H), 3.33-3.20 (m, 2H), 3.12 (ddd, J = 12.8, 8.9, 6.6 Hz, 1H), 2.55 (s, 3H), 1.82-1.63 (m, 2H), 1.57-1.42 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H), 0.84-0.75 (m, 2H), 0.69-0.58 (m, 2H). ESI-MS (m / z): 458.1 [M + H] ⁺ .

2-(((Butylsulfinyl) methyl) thio) -4- (1-cyclopropyl-2-methyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile H ₂ O ₂ oxidation of (((butylthio) methyl) thio) -4- (1-cyclopropyl-2-methyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile Via the synthetic procedure described for the preparation of analog SW209415 in 99% isolated yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (s, 1H), 7.98 (d, J = 3.1 Hz, 1H), 7.60 (d, J = 3.1 Hz, 1H), 7. 43 (s, 1H), 4.73 (d, J = 13.1 Hz, 1H), 4.39 (d, J = 13.1 Hz, 1H), 3.49 (tt, J = 7.2, 4 0.0 Hz, 1H), 2.98 (dt, J = 12.9, 8.1 Hz, 1H), 2.82 (dt, J = 12.9, 7.3 Hz, 1H), 2.57 (s, 3H), 1.84 (p, J = 7.7 Hz, 2H), 1.61-1.37 (m, 2H), 1.17-1.07 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H), 0.70-0.58 (m, 2H). ESI-MS (m / z): 458.1 [M + H] ⁺ .

2-(((Butylthio) methyl) thio) -4- (1-cyclopropyl-2-methyl-1H-imidazol-5-yl) -6- (thiazol-2-yl) nicotinonitrile is obtained as (E) 3- (1-Cyclopropyl-2-methyl-1H-imidazol-5-yl) -1- (thiazol-2-yl) prop-2-en-1-one, 2-cyanoethanethioamide and butyl (chloro Prepared from methyl) sulfane in 48% isolated yield using the synthetic procedure described for the preparation of analog SW209415. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.00 (s, 1H), 7.96 (d, J = 3.1 Hz, 1H), 7.57 (d, J = 3.1 Hz, 1H), 7. 38 (s, 1H), 4.51 (s, 2H), 3.48 (tt, J = 7.2, 3.9 Hz, 1H), 2.76 (t, J = 7.3 Hz, 2H), 2.56 (s, 3H), 1.74-1.54 (m, 2H), 1.50-1.33 (m, 2H), 1.14-1.02 (m, 2H),. 91 (t, J = 7.3 Hz, 3H), 0.69-0.53 (m, 2H). ESI-MS (m / z): 442.1 [M + H] ^< +>.

(E) -3- (1-Cyclopropyl-2-methyl-1H-imidazol-5-yl) -1- (thiazol-2-yl) prop-2-en-1-one is substituted with 1- (4- From methylthiazol-2-yl) -2- (triphenyl-λ5-phosphanylidene) ethane-1-one and 1-cyclopropyl-2-methyl-1H-imidazole-5-carbaldehyde ⁴ to Wittig (4 days) reaction Via the synthetic procedure described for the preparation of analog SW209415 in 48% isolated yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.09 (d, J = 16.0 Hz, 1 H), 8.03 (d, J = 3.1, ¹ H), 7.75 (d, J = 15.9 Hz) 1H), 7.68 (d, J = 3.0 Hz, 1H), 7.56 (s, 1H), 3.23-3.06 (m, 1H), 2.52 (s, 3H), 1.38-1.26 (m, 2H), 1.05-0.94 (m, 2H). ESI-MS (m / z): 260.1 [M + H] ^< +>.

1-Cyclopropyl-2-methyl-1H-imidazole-5-carbaldehyde ⁴ was prepared from ethyl ethaneimidate hydrochloride, cyclopropylamine and bromomalonaldehyde. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.69 (s, 1H), 7.62 (s, 1H), 3.22 (tt, J = 7.4, 3.9 Hz, 1H), 2.52 ( s, 3H), 1.33-1.16 (m, 2H), 1.02-0.83 (m, 2H). ESI-MS (m / z): 151.1 [M + H] ^< +>.

SW218520.2- (cyclohexylsulfinyl) -4-phenyl-6- (thiophen-2-yl) thieno [2,3-b] pyridin-3-amine is converted to 2-(((cyclohexylsulfinyl) methyl) thio)- Prepared via the cyclization reaction of 4-phenyl-6- (thiophen-2-yl) nicotinonitrile in 84% isolated yield using the synthetic procedure described for the preparation of analog SW209415. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 7.69 (dd, J = 3.7, 1.1 Hz, 1 H), 7.65-7.38 (m, 7H), 7.15 (dd, J = 5.1, 3.7 Hz, 1H), 4.54 (s, 2H), 3.15 (tt, J = 11.3, 3.6 Hz, 1H), 2.31-2.16 (m, 1H), 1.98-1.87 (m, 1H), 1.88-1.75 (m, 1H), 1.75-1.63 (m, 1H), 1.64-1.45 ( m, 2H), 1.45-1.25 (m, 4H). ESI-MS (m / z): 439.1 [M + H] ⁺ .

2-((((cyclohexylsulfinyl) methyl) thio) -4-phenyl-6- (thiophen-2-yl) nicotinonitrile is converted to 2-(((cyclohexylthio) methyl) thio) -4-phenyl-6- Prepared using the synthetic procedure described for the preparation of analog SW209415 in 70% isolated yield via H ₂ O ₂ oxidation of (thiophen-2-yl) nicotinonitrile. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.77 (dt, J = 3.8, 1.1 Hz, 1H), 7.67-7.58 (m, 2H), 7.58-7.50 (m 4H), 7.47 (s, 1H), 7.16 (ddd, J = 4.9, 3.8, 1.0 Hz, 1H), 4.65 (d, J = 13.2 Hz, 1H) 4.58 (d, J = 13.1 Hz, 1H), 2.84 (tt, J = 11.8, 3.8 Hz, 1H), 2.15-1.82 (m, 4H), 1. 79-1.53 (m, 3H), 1.51-1.18 (m, 3H). ESI-MS (m / z): 439.1 [M + H] ⁺ .

2-((((Cyclohexylthio) methyl) thio) -4-phenyl-6- (thiophen-2-yl) nicotinonitrile. 4-phenyl-6- (thiophen-2-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile (Patent: WO2013 / 158649A1, 2013) (0.17 mmol, 50 mg), (chloromethyl) A mixture of (cyclohexyl) sulfane (0.17 mmol, 28 mg, 1.0 equiv) and Et ₃ N (0.34 mmol, 34 mg, 2.0 equiv) was refluxed in dry CH ₃ CN (1 mL) for 20 minutes. . The reaction mixture was then diluted with EtOAc and water. The organic phase was separated and the aqueous layer was extracted twice with EtOAc. The extracts were combined, washed with saturated NaCl solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give 52 mg of the planned product (73%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.71 (dd, J = 3.8, 1.1 Hz, 1H), 7.65-7.57 (m, 2H), 7.57-7.47 (m 4H), 7.41 (s, 1H), 7.15 (dd, J = 5.0, 3.8 Hz, 1H), 4.56 (s, 2H), 3.05-2.90 (m) 1H), 2.15-1.98 (m, 2H), 1.87-1.73 (m, 2H), 1.49-1.17 (m, 6H). ESI-MS (m / z): 423.1 [M + H] ⁺ .

SW218521.2- (butylsulfinyl) -4- (1-ethyl-1H-imidazol-2-yl) -6- (thiazol-2-yl) thieno [2,3-b] pyridin-3-amine is converted to 2 Via the cyclization of-(((butylsulfinyl) methyl) thio) -4- (1-ethyl-1H-imidazol-2-yl) -6- (thiazol-2-yl) nicotinonitrile Prepared using the synthetic procedure described for the preparation of SW209415. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 8.18 (s, 1H), 7.96 (d, J = 3.2 Hz, 1H), 7.57 (d, J = 3.1 Hz, 1H), 7.28 (s, 1H), 7.27 (s, 1H), 5.78 (s, 2H), 4.11 (q, J = 7.3 Hz, 2H), 3.25 (ddd, J = 12.7, 9.2, 6.0 Hz, 1H), 3.10 (ddd, J = 12.8, 9.3, 6.4 Hz, 1H), 1.85-1.63 (m, 2H) 1.56-1.46 (m, 2H), 1.44 (t, J = 7.3 Hz, 3H), 0.95 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 432.1 [M + H] ^< +>.

2-((((Butylsulfinyl) methyl) thio) -4- (1-ethyl-1H-imidazol-2-yl) -6- (thiazol-2-yl) nicotinonitrile is converted to 2-(((butylthio) Methyl) thio) -4- (1-ethyl-1H-imidazol-2-yl) -6- (thiazol-2-yl) nicotinonitrile via H ₂ O ₂ oxidation in 97% isolated yield Prepared using the synthetic procedure described for the preparation of analog SW209415. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.12 (s, 1H), 7.99 (d, J = 3.1 Hz, 1H), 7.61 (d, J = 3.1 Hz, 1H), 7. 31 (s, 1H), 7.20 (s, 1H), 4.74 (d, J = 13.1 Hz, 1H), 4.39 (d, J = 13.1 Hz, 1H), 4.12 ( q, J = 7.3 Hz, 2H), 2.98 (dt, J = 12.9, 8.1 Hz, 1H), 2.82 (dt, J = 12.8, 7.3 Hz, 1H), 1 .83 (h, J = 6.9, 6.2 Hz, 2H), 1.65-1.40 (m, 5H), 0.96 (t, J = 7.4 Hz, 3H). ESI-MS (m / z): 432.1 [M + H] ^< +>.

2-(((Butylthio) methyl) thio) -4- (1-ethyl-1H-imidazol-2-yl) -6- (thiazol-2-yl) nicotinonitrile is converted to (E) -3- (1 -25% isolated from ethyl-1H-imidazol-2-yl) -1- (thiazol-2-yl) prop-2-en-1-one, 2-cyanoethanethioamide and butyl (chloromethyl) sulfane Prepared using the synthetic procedure described for the preparation of analog SW209415. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04 (s, 1H), 7.98 (d, J = 3.1 Hz, 1H), 7.58 (d, J = 3.2 Hz, 1H), 7. 30 (s, 1H), 7.18 (s, 1H), 4.52 (s, 2H), 4.10 (q, J = 7.3 Hz, 2H), 2.75 (t, J = 7. 4 Hz, 2H), 1.65 (p, J = 7.3 Hz, 2H), 1.54-1.36 (m, 5H), 0.92 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 416.1 [M + H] ⁺ .

(E) -3- (1-Ethyl-1H-imidazol-2-yl) -1- (thiazol-2-yl) prop-2-en-1-one was converted to 1- (4-methylthiazol-2-one). Yl) -2- (triphenyl-λ5-phosphanylidene) ethane-1-one (1.0 equiv) and 1-ethyl-1H-imidazole-2-carbaldehyde ⁵ via the Wittig reaction (24 hours), Prepared using the synthetic procedure described for the preparation of analog SW209415 in 56% isolated yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.26 (d, J = 15.4 Hz, 1H), 8.03 (d, J = 3.0 Hz, 1 H), 7.82 (d, J = 15.4 Hz) 1H), 7.67 (d, J = 3.0 Hz, 1H), 7.22 (s, 1H), 7.07 (d, J = 1.2 Hz, 1H), 4.15 (q, J = 7.4 Hz, 2H), 1.45 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 234.1 [M + H] ^< +>.

SW218522.2- (butylsulfinyl) -6- (thiazol-2-yl) -4- (1,4,5-trimethyl-1H-imidazol-2-yl) thieno [2,3-b] pyridine-3- The amine is attached to the 2-(((butylsulfinyl) methyl) thio) -6- (thiazol-2-yl) -4- (1,4,5-trimethyl-1H-imidazol-2-yl) nicotinonitrile ring. Prepared using the synthetic procedure described for the preparation of analog SW209415 in 96% isolated yield via the isomerization reaction. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 8.13 (s, 1H), 7.95 (d, J = 3.2 Hz, 1H), 7.56 (d, J = 3.2 Hz, 1H), 6.26 (s, 2H), 3.66 (s, 3H), 3.25 (ddd, J = 12.7, 9.2, 5.9 Hz, 1H), 3.10 (ddd, J = 12) .7, 9.3, 6.3 Hz, 1H), 2.27 (s, 3H), 2.24 (s, 3H), 1.89-1.64 (m, 2H), 1.55-1 .37 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 446.1 [M + H] ⁺ .

2-(((Butylsulfinyl) methyl) thio) -6- (thiazol-2-yl) -4- (1,4,5-trimethyl-1H-imidazol-2-yl) nicotinonitrile is converted to 2- ( Via H ₂ O ₂ oxidation of ((butylthio) methyl) thio) -6- (thiazol-2-yl) -4- (1,4,5-trimethyl-1H-imidazol-2-yl) nicotinonitrile Prepared using the synthetic procedure described for the preparation of analog SW209415 in 95% isolated yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (s, 1H), 7.98 (d, J = 3.1 Hz, 1H), 7.58 (d, J = 3.1 Hz, 1H), 4. 75 (d, J = 13.1 Hz, 1H), 4.37 (d, J = 13.0 Hz, 1H), 3.64 (s, 3H), 2.97 (dt, J = 12.6, 8 .2 Hz, 1 H), 2.81 (dt, J = 12.4, 7.1 Hz, 1 H), 2.24 (s, 6 H), 1.94-1.73 (m, 2 H), 1.63 -1.39 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). ESI-MS (m / z): 446.1 [M + H] ⁺ .

2-(((Butylthio) methyl) thio) -6- (thiazol-2-yl) -4- (1,4,5-trimethyl-1H-imidazol-2-yl) nicotinonitrile is converted to (E)- 46% simple from 1- (thiazol-2-yl) -3- (1,4,5-trimethyl-1H-imidazol-2-yl) prop-2-en-1-one and butyl (chloromethyl) sulfane Prepared using the synthetic procedure described for the preparation of analog SW209415 in release yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.05 (s, 1H), 7.97 (d, J = 2.9 Hz, 1H), 7.56 (d, J = 2.9 Hz, 1H), 4. 52 (s, 2H), 3.61 (s, 3H), 2.75 (t, J = 7.4 Hz, 3H), 2.23 (s, 6H), 1.74-1.57 (m, 2H), 1.49-1.36 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H). ESI-MS (m / z): 430.1 [M + H] ^< +>.

(E) -1- (thiazol-2-yl) -3- (1,4,5-trimethyl-1H-imidazol-2-yl) prop-2-en-1-one was converted to 1- (4-methyl Wittig reaction from thiazol-2-yl) -2- (triphenyl-λ5-phosphanylidene) ethane-1-one (1.0 equiv) and 1,4,5-trimethyl-1H-imidazole-2-carbaldehyde ⁶ (24 hours) with 31% isolated yield using the synthetic procedure described for the preparation of analog SW209415. ESI-MS (m / z): 248.1 [M + H] ^< +>.

Although the invention has been particularly shown and described with reference to preferred embodiments thereof, those skilled in the art will recognize that various changes in form and detail are encompassed therein by the appended claims. It will be understood that this is possible without departing from the scope of the invention as described. All patents, publications and references cited in the above specification are hereby incorporated by reference in their entirety.
1 Lorente, A .; Navio, J .; L. Garcia; Vaquero, J .; J. et al. Soto, J .; L. J. et al. Heterocycl. Chem. , 1985, 22, 49.

2 Hoyt, A.M. L. Blakemore, P .; R. Tetrahedron Lett. 2015, 56. 2980.

3 Girgis, A.M. S. Mishriky, N .; Farag, A .; M.M. El-Eraky, W .; I. Farag, H .; Eur. J. et al. Med. Chem. 2008, 43, 1818.

4 Patents: BOEHRINGER INGELHEIM PHARMACEUTICALS, INC. : WO2005 / 90333 A1, 2005.

5 Seto, M .; Miyamoto, N .; Aikawa, K .; Aramaki, Y .; Kanzaki, N .; Iizawa, Y .; Baba, M .; Shirai, M .; Bioorg. Med. Chem. , 2005, 13, 363

6 Zhou, Y .; Gong, Y .; Eur. J. et al. Org. Chem. 2011, 30, 6092

Claims (99)

Compounds having formula (I), and pharmaceutically acceptable salts thereof:

Where n = 0-2;
X ⁶ is N or CR ^c ;
R ¹ is — (CH ₂ ) n ₁ CH ₃ (n ₁ = 0-7),

Where n ₂ = 0-6 and X is one of the following:
CF _y H _z (y + z = 3), CCl _y H _z (y + z = 3), OH, OAc, OMe, R ⁷¹ , OR ⁷² , CN, N (R ⁷³ ) ₂ ,

(N ₃ = 0-5, m = 1-5), and

(N ₄ = 0-5)
Selected from the group consisting of branched or straight chain alkyls including:
R ⁵ is selected from the group consisting of H, OH, Cl, F, NH ₂ , N (R ⁷⁶ ) ₂ , and OR ⁷⁷ _;
R ⁶ and R ⁷ can each independently be one of the following:

Each ^{_{R 8, R 9, R 10}} , R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19, R 20, R 21, R 22, R 23, R ^{_{24, R 25, R 26,}} R 27a, R 27b, R 28, R 29, R 30, R 31, R 32, R 33, R 34, R 35, R 36, R 37, R 38, R 39, ^{_{R 40, R 41, R 42}} , R 43, R 44, R 45, R 46, R 47, R 48, R 49, R 50, R 51, R 52, R 53, R 54, R 55, R 56 ^{_{, R 57, R 58, R}} 59, R 60, R 61, R 62, R 63, R 64, R 65, R 66, R 67, R 68, R 69, R 70, R 71, R 72, R ^{7 3} _, R ⁷⁴ _, R ⁷⁶ , R ⁷⁷ , and R ^c are the same or different and are hydrogen, substituted or unsubstituted C ₁ -C ₂₄ alkyl, C ₂ -C ₂₄ alkenyl, C ₂ -C ₂₄ alkynyl, C _3- C ₂₀ aryl, heterocycloalkenyl containing 5-6 ring atoms, wherein 1-3 ring atoms are N, NH, N (C ₁ -C ₆ alkyl), NC (O) ( C ₁ -C ₆ alkyl), independently selected from O, and S), heteroaryl or heterocyclyl containing 5-14 ring atoms, wherein 1-6 ring atoms are N, NH , N (C ₁ -C ₃ alkyl), independently selected from O and S), C ₆ -C ₂₄ alkaryl, C ₆ -C ₂₄ aralkyl, halo, silyl, hydroxyl, sulfhydryl, C ₁ -C ₂₄ alkoxy , _C 2 _{-C 24 alkenyloxy,} C 2 _{-C 24 alkynyloxy,} C 5 _{-C 20} aryloxy, acyl _(e.g., C 2 _{-C 24} alkylcarbonyl (--CO- alkyl) and _C 6 _{-C 20} aryl Carbonyl (—CO-aryl)), acyloxy (—O-acyl), C ₂ -C ₂₄ alkoxycarbonyl (— (CO) —O-alkyl), C ₆ -C ₂₀ aryloxycarbonyl (— (CO) —O) - _aryl), C 2 _{-C 24} alkylcarbonyl diisocyanatohexane (-O- (CO) -O- _alkyl), C 6 _{-C 20} aryl carbonium diisocyanatohexane (-O- (CO) -O- aryl), carboxy (-COOH ), Carboxylato (—COO ⁻ ), carbamoyl (— (CO) —NH ₂ ), C ₁ -C ₂₄ alkyl-carbamoyl (— (CO)) -NH _(C 1 _{-C 24} alkyl)), arylcarbamoyl (- (CO) -NH- aryl), thiocarbamoyl _{(- (CS) -NH 2)} , carbamide _{(-NH- (CO) -NH 2)} , cyano (-CN), isocyano ^(-N + C ^-), cyanato (-O-CN), isocyanato ^{(-O-N + = C -} ), isothiocyanato (-S-CN), azido (-N = ^{N +} = N ^-), formyl (- (CO) - H) , thioformyl (- (CS) - H) , amino _{(--NH 2), C 1 -C} 24 _alkylamino, C 5 _{-C 20 arylamino,} C 2 _{-C 24} alkylamido (-NH- (CO) - _alkyl), C 6 _{-C 20} aryl amide (-NH- (CO) - aryl), sulfonamide _{(-SO 2} N _(R) 2 Where R is independently H, alkyl, aryl or heteroaryl), imino (—CR═NH, wherein R is hydrogen, C ₁ -C ₂₄ alkyl, C ₅ -C ₂₀ aryl, C ₆ -C ₂₄ alkaryl, C _6. -C ₂₄ aralkyl, and the like), alkylimino (-CR = N (alkyl), wherein, R = hydrogen, alkyl, aryl, alkaryl, aralkyl, and the like), arylimino (-CR = N (aryl ), Wherein R = hydrogen, alkyl, aryl, alkaryl, etc.), nitro (—NO ₂ ), nitroso (—NO), sulfo (—SO ₂ —OH), sulfonate (—SO ₂ —O ^—) _), C 1 _{-C 24} alkylsulfanyl (-S- alkyl; also termed "alkylthio"), arylsulfanyl (-S- aryl; "arylthio" both _Barrel), C 1 _{-C 24} alkylsulfinyl (- (SO) - _alkyl), C 5 _{-C 20} arylsulfinyl (- (SO) - _aryl), C 1 _{-C 24} alkylsulfonyl (-SO ₂ - alkyl), C ₅ -C ₂₀ arylsulfonyl (—SO ₂ -aryl), sulfonamide (—SO ₂ —NH ₂ , —SO ₂ NY ₂ , wherein Y is independently H, aryl, or alkyl) , Phosphono (—P (O) (OH) ₂ ), phosphonate (—P (O) (O ⁻ ) ₂ ), phosphinate (—P (O) (O ⁻ )), phospho (—PO ₂ ), phosphino ( --PH _2), polyalkyl ethers _{(- [(CH 2) n} O] m), phosphate, phosphoric acid ester _{[-OP (O) (oR)} 2, where, R = H, methyl or other Alkyl], selected in an amino acid or physiological pH positive or incorporated group other portions that are expected to have a negative charge, and independently from the group consisting of;
When R ⁶ is H, unsubstituted thiophene, or unsubstituted thiazole, and R ¹ is butyl, R ⁷ is not hydrogen; and R ⁶ is H, or unsubstituted phenyl, thiophene, or thiazole And R ¹ is benzyl or (CH ₂ ) n ₅ (CH ₃ ) (n ₅ = 0-5), then R ⁷ is not unsubstituted phenyl. The compound according to claim 1, wherein X ⁶ is N or CH. R ⁶ includes 5-6 ring atoms, a substituted or unsubstituted heterocyclyl, A compound according to any one of claims 1-2. The compound according to any one of claims 1 to 3, wherein R ⁶ is substituted or unsubstituted thiophene, thiazole, oxazole, imidazole, pyridine, or phenyl.   The compound according to any one of claims 1 to 4, wherein n is 1. R ⁷ is H, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl, alkyl, or carboxy, such as carboxylic acid (—CO ₂ H), carboxy ester (—CO ₂ alkyl) and carboxamide [ -CON (H) (alkyl), or _-CO 2 N is selected from the group consisting of _{(alkyl) 2]} the compound according to claim 1. A compound according to any of claims 1 to 6, wherein R ⁷ is not

Compounds having formula (III), and pharmaceutically acceptable salts thereof:

Where n = 0-2;
X ⁶ is N or CR ^c ;
X ⁷ is N or C;
R ¹ is — (CH ₂ ) n ₁ CH ₃ (n ₁ = 0-7),

Where n ₂ = 0-6 and X is one of the following:
CF _y H _z (y + z = 3), CCl _y H _z (y + z = 3), OH, OAc, OMe, R ⁷¹ , OR ⁷² , CN, N (R ⁷³ ) ₂ ,

(N ₃ = 0-5, m = 1-5), and

(N ₄ = 0-5)
Selected from the group consisting of branched or straight chain alkyls including:
R ⁵ is selected from the group consisting of H, OH, Cl, F, NH ₂ , N (R ⁷⁶ ) ₂ , and OR ⁷⁷ _;
Each R ⁷ can independently be one of the following:

Each ^{_{R 8, R 9, R 10}} , R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19, R 20, R 21, R 22, R 23, R ^{_{24, R 25, R 26,}} R 27a, R 27b, R 28, R 29, R 30, R 31, R 32, R 33, R 34, R 35, R 36, R 37, R 38, R 39, R ⁴⁰ _, R ⁴¹ _, R ⁴² _, R ⁴³ _, R ⁴⁴ _, R ⁴⁵ _, R ⁴⁶ _, R ⁴⁷ _, R ⁷¹ _, R ⁷² _, R ⁷³ _, R ⁷⁴ _, R ⁷⁶ , R ⁷⁷ , R ^c , and R ^d are the same or different, and, Haitai containing hydrogen, substituted or unsubstituted _C 1 _{-C 24 alkyl,} C 2 _{-C 24 alkenyl,} C 2 _{-C 24 alkynyl,} C 3 _{-C 20} aryl, a 5-6 ring atoms Rocycloalkenyl, wherein 1-3 ring atoms are independent of N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O, and S Heteroaryl or heterocyclyl containing 5-14 ring atoms, wherein 1-6 ring atoms are N, NH, N (C ₁ -C ₃ alkyl), O, and S C ₆ -C ₂₄ alkaryl, C ₆ -C ₂₄ aralkyl, halo, silyl, hydroxyl, sulfhydryl, C ₁ -C ₂₄ alkoxy, C ₂ -C ₂₄ alkenyloxy, C ₂ -C _{24 alkynyloxy,} C 5 _{-C 20} aryloxy, acyl _(e.g., C 2 _{-C 24} alkylcarbonyl (--CO- alkyl) and _C 6 _{-C 20} arylcarbonyl (-CO- aryl ), Acyloxy (-O- _acyl), C 2 _{-C 24} alkoxycarbonyl (- (CO) -O- _alkyl), C 6 _{-C 20} aryloxycarbonyl (- (CO) -O- aryl), _{C 2} - C ₂₄ alkyl carbonate (—O— (CO) —O-alkyl), C ₆ -C ₂₀ aryl carbonate (—O— (CO) —O-aryl), carboxy (—COOH), carboxylate (—COO ^-), carbamoyl _{(- (CO) - NH 2} ), C 1 -C 24 alkyl - carbamoyl _{(- (CO) -NH (C} 1 -C 24 alkyl)), arylcarbamoyl (- (CO) -NH- aryl), thiocarbamoyl _{(- (CS) -NH 2)} , carbamide _{(-NH- (CO) -NH 2)} , cyano (-CN), isocyano ^(-N + C ^-), shea Preparative (-O-CN), isocyanato ^{(-O-N + = C -} ), isothiocyanato (-S-CN), azido ^{(-N = N + = N -} ), formyl (- (CO) - H ), thioformyl (- (CS) - H) , amino _{(--NH 2), C 1 -C} 24 _alkylamino, C 5 _{-C 20 arylamino,} C 2 _{-C 24} alkylamido (-NH- ( CO) - _alkyl), C 6 _{-C 20} aryl amide (-NH- (CO) - aryl), sulfonamide _{(-SO 2 N (R) 2} , wherein, R is independently H, alkyl, aryl, or Is heteroaryl), imino (—CR═NH, where R is hydrogen, C ₁ -C ₂₄ alkyl, C ₅ -C ₂₀ aryl, C ₆ -C ₂₄ alkaryl, C ₆ -C ₂₄ aralkyl, etc. ), Alkylimino ( CR = N (alkyl), where R = hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (—CR = N (aryl), where R = hydrogen, alkyl, aryl, alkaryl) ), Nitro (—NO ₂ ), nitroso (—NO), sulfo (—SO ₂ —OH), sulfonate (—SO ₂ —O ⁻ ), C ₁ -C ₂₄ alkylsulfanyl (—S-alkyl). ; also referred to as "alkylthio"), arylsulfanyl (-S- aryl; also termed _"arylthio"), C 1 _{-C 24} alkylsulfinyl (- (SO) - _alkyl), C 5 _{-C 20} arylsulfinyl (- (SO ) - _aryl), C 1 _{-C 24} alkylsulfonyl (-SO ₂ - _alkyl), C 5 _{-C 20} arylsulfonyl ( SO ₂ - aryl), sulfonamide _{(-SO 2 -NH 2, -SO 2} NY 2 ( in the formula, Y is independently H, Aririru (Arlyl) or alkyl), phosphono (-P (O) ( OH) ₂ ), phosphonate (—P (O) (O ⁻ ) ₂ ), phosphinate (—P (O) (O ⁻ )), phospho (—PO ₂ ), phosphino (—PH ₂ ), polyalkyl ether (— [(CH ₂ ) _n O] _m ), phosphate, phosphate ester [—OP (O) (OR) ₂ , where R = H, methyl or other alkyl], amino acid or physiological pH Independently selected from the group consisting of groups incorporating other moieties expected to have a positive or negative charge at and combinations thereof;
R ⁷ is not:

X ⁶ is N or CH, A compound according to claim 8.   The compound according to any one of claims 8 to 9, wherein n is 1. The compound according to any one of claims 1 to 10, wherein the compound does not have a formula selected from the group consisting of: and a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 having a formula selected from the group consisting of: and a pharmaceutically acceptable salt thereof.

  Use of a compound according to any of claims 1 to 12 in the preparation of a pharmaceutical composition.   Use of a compound according to any of claims 1-12 as a short chain dehydrogenase inhibitor for inhibiting the activity of a short chain dehydrogenase enzyme.   Use of a compound according to any of claims 1 to 12 as a 15-PGDH inhibitor for inhibiting the activity of a 15-PGDH enzyme. The inhibitor has an IC ₅₀ of less than 1 μM, preferably an IC ₅₀ of less than 250 nM, more preferably an IC ₅₀ of less than 50 nM, more preferably 10 nM at a recombinant 15-PGDH concentration of about 5 nM to about 10 nM. with _{an IC 50} of less than, more preferably with _{an IC 50} of less than 5 nM, inhibit the enzymatic activity of recombinant 15-PGDH, use of any of claims 14 or 15.   17. Use according to any of claims 13 to 16, wherein the inhibitor is administered to a subject's tissue in an amount effective to increase prostaglandin levels in the tissue.   Use according to any of claims 13 to 16, wherein the inhibitor is provided in a topical composition.   The inhibitor is applied to the subject's skin to promote and / or stimulate skin pigmentation and / or hair growth and / or inhibit hair loss and / or treat skin damage or inflammation. Use according to any of claims 13-16.   17. Use according to any of claims 13 to 16, wherein the inhibitor is administered to a subject to promote wound healing, tissue repair, and / or tissue regeneration.   The inhibitors include oral ulcer, periodontal disease, colitis, ulcerative colitis, gastrointestinal ulcer, inflammatory bowel disease, blood circulation disorder, Raynaud's disease, Buerger's disease, diabetic neuropathy, pulmonary artery hypertension, cardiovascular disease, and kidney 17. Use according to any of claims 13-16, wherein the use is administered to a subject to treat at least one of the diseases.   Use according to any of claims 13 to 16, wherein the inhibitor is administered to a subject in combination with a prostanoid agonist for the purpose of enhancing the therapeutic effect of the agonist in a prostaglandin responsive condition.   The use according to any of claims 13 to 16, wherein the inhibitor is administered to the tissue of the subject to increase tissue stem cells.   The inhibitor is administered to a tissue transplant donor, bone marrow transplant donor, and / or hematopoietic stem cell donor to increase the fitness of the donor tissue graft, donor bone marrow transplant, and / or donor hematopoietic stem cell transplant Use according to any of claims 13 to 16, wherein   The use according to any of claims 13 to 16, wherein the inhibitor is administered to the bone marrow of a subject to increase stem cells in the subject.   17. Use according to any of claims 13 to 16, wherein the inhibitor is administered to the bone marrow of a subject to increase the fitness of the bone marrow as a donor graft.   17. Use according to any of claims 13 to 16, wherein the inhibitor is administered to a hematopoietic stem cell preparation of a subject to increase the fitness of the stem cell preparation as a donor graft.   17. Use according to any of claims 13 to 16, wherein the inhibitor is administered to a peripheral blood hematopoietic stem cell preparation of a subject to increase the fitness of the stem cell preparation as a donor graft.   17. Use according to any of claims 13 to 16, wherein the inhibitor is administered to a cord blood stem cell preparation to increase the fitness of the stem cell preparation as a donor graft.   17. Use according to any of claims 13 to 16, wherein the inhibitor is administered to a preparation of cord blood stem cells in order to reduce the number of cord blood units required for transplantation.   17. Use according to any of claims 13 to 16, wherein the inhibitor is administered to a subject to alleviate tissue graft rejection.   17. Use according to any of claims 13 to 16, wherein the inhibitor is administered to a subject to enhance tissue and / or bone marrow graft survival.   14. The inhibitor is administered to a subject to enhance bone marrow graft survival following treatment with the subject or the subject's bone marrow with radiation therapy, chemotherapy, or immunosuppressive therapy. Use according to any of -16.   17. Use according to any of claims 13 to 16, wherein the inhibitor is administered to a subject in order to enhance engraftment of progenitor stem cell grafts, hematopoietic stem cell grafts, or umbilical cord blood stem cell grafts.   The inhibitor may be used to enhance the engraftment of hematopoietic stem cell grafts or umbilical cord stem cell grafts after treatment with the subject or the subject's bone marrow with radiotherapy, chemotherapy, or immunosuppressive therapy. Use according to any of claims 13 to 16, wherein   17. Use according to any of claims 13 to 16, wherein the inhibitor is administered to a subject in order to reduce the number of cord blood units required for transplantation into the subject.   The inhibitor is administered to a recipient of tissue graft transplant, bone marrow transplant, and / or hematopoietic stem cell transplant, or umbilical cord stem cell transplant to reduce administration of other treatments or growth factors. 16. Use according to any of 16.   17. Use according to any of claims 13 to 16, wherein the inhibitor is administered to a subject or a subject's tissue graft to alleviate graft rejection.   17. Use according to any of claims 13 to 16, wherein the inhibitor is administered to a subject or a subject's tissue graft to enhance graft survival.   The inhibitor is administered to a subject or a tissue graft of the subject to enhance graft survival after treatment with the subject or the bone marrow of the subject by radiation therapy, chemotherapy, or immunosuppressive therapy Use according to any of claims 13 to 16, wherein   17. Use according to any of claims 13 to 16, wherein the inhibitor is administered to confer resistance to the toxicity or lethal effects of exposure to radiation to the subject or to the subject's bone marrow.   The inhibitor is administered to confer resistance to a toxic effect of cytoxan, a toxic effect of fludarabine, a toxic effect of chemotherapy, or a toxic effect of immunosuppressive therapy to a subject or bone marrow of the subject, Item 15. The use according to any one of Items 13 to 16.   17. Use according to any of claims 13 to 16, wherein the inhibitor is administered to a subject or the bone marrow of a subject to reduce infection.   The use according to any of claims 13 to 16, wherein the inhibitor is administered to a subject in order to increase the neutrophil count after hematopoietic cell transplantation with bone marrow, hematopoietic stem cells or umbilical cord blood.   17. The inhibitor of claim 13-16, wherein the inhibitor is administered to a subject to increase neutrophil count following chemotherapy administration or radiation therapy in a subject having neutropia. Use as described in any one.   The inhibitors include aplastic anemia, myelodysplasia, myelofibrosis, neutropenia due to other bone marrow diseases, drug-induced neutropenia, autoimmune neutropenia, idiopathic favorable 17. Use according to any of claims 13 to 16, administered to a subject to increase neutrophil count in a subject having neutropenia, or neutropenia after viral infection.   17. Use according to any of claims 13 to 16, wherein the inhibitor is administered to a subject to increase the neutrophil count in a subject having neutropia.   The use according to any of claims 13 to 16, wherein the inhibitor is administered to a subject in order to increase the platelet count after hematopoietic cell transplantation with bone marrow, hematopoietic stem cells or umbilical cord blood.   17. Use according to any of claims 13 to 16, wherein the inhibitor is administered to a subject to increase platelet count in a subject with thrombocytopenia after chemotherapy administration or radiation therapy.   Said inhibitors include aplastic anemia, myelodysplasia, myelofibrosis, thrombocytopenia due to other bone marrow diseases, drug-induced thrombocytopenia, autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, idiopathic 17. Use according to any of claims 13-16, wherein the subject is administered to a subject to increase platelet count in a subject having systemic thrombocytopenia, or thrombocytopenia after viral infection.   17. Use according to any of claims 13 to 16, wherein the inhibitor is administered to a subject to increase platelet count in a subject with thrombocytopenia.   17. The inhibitor of any of claims 13-16, wherein the inhibitor is administered to a subject to increase red blood cell count, or hematocrit, or hemoglobin levels after hematopoietic cell transplantation with bone marrow, hematopoietic stem cells, or umbilical cord blood. Use as described in.   17. The inhibitor of any of claims 13-16, wherein the inhibitor is administered to a subject to increase red blood cell count, or hematocrit, or hemoglobin level in a subject with anemia following chemotherapy or radiation therapy. Use as described in.   The inhibitor may be aplastic anemia, myelodysplasia, myelofibrosis, anemia due to other disorders of bone marrow, drug anemia, immune-mediated anemia, anemia of chronic disease, anemia after viral infection, or unknown cause 17. Use according to any of claims 13 to 16, wherein the subject is administered to a subject to increase erythrocyte count, or hematocrit, or hemoglobin level count in a subject with multiple anemias.   17. Use according to any of claims 13 to 16, wherein the inhibitor is administered to a subject to increase red blood cell count, or hematocrit, or hemoglobin levels in a subject with anemia.   The use according to any of claims 13 to 16, wherein the inhibitor is administered to a subject to increase bone marrow stem cells after bone marrow, hematopoietic stem cells or hematopoietic cell transplantation with umbilical cord blood.   17. Use according to any of claims 13 to 16, wherein the inhibitor is administered to a subject to increase bone marrow stem cells in the subject after chemotherapy administration or radiation therapy.   The inhibitor has aplastic anemia, myelodysplasia, myelofibrosis, other disorders of the bone marrow, drug-induced cytopenia, immunocytopenia, cytopenia after viral infection, or cytopenia 17. Use according to any of claims 13-16, wherein the use is administered to a subject to increase bone marrow stem cells in the subject.   The inhibitor is administered to a subject to increase responsiveness to cytokines in the presence of cytopenia, and cytopenias include any of the following: neutropenia, thrombocytopenia 17. Use according to any of claims 13 to 16, wherein the lymphopenia and anemia; and the cytokine has an increased responsiveness enhanced by a 15-PGDH inhibitor comprising any of the following: G-CSF , GM-CSF, EPO, IL-3, IL-6, TPO, TPO-RA (thrombopoietin receptor agonist), and SCF.   17. Use according to any of claims 13 to 16, wherein the inhibitor is administered to a subject or to the bone marrow of a subject to reduce radiation-derived lung toxicity.   17. The inhibitor is administered to a subject to increase bone density, treat osteoporosis, promote fracture healing, or promote healing after bone surgery or joint replacement. Use as described in any of the above.   17. Use according to any of claims 13 to 16, wherein the inhibitor is administered to a subject to promote bone healing for bone implants, artificial implants, dental implants and transplanted bone.   The use according to any of claims 13 to 16, wherein the inhibitor is administered to a subject or a subject's intestine to increase stem cells in the intestine.   The inhibitor increases the number of stem cells in the gut in the subject or the gut of the subject, and toxicity, lethal, or mucositis resulting from the toxicity or lethal effects of exposure to radiation or treatment with chemotherapy Use according to any of claims 13 to 16, administered to confer resistance to an effect.   The inhibitor is administered to confer resistance to the toxicity or lethal effects of radiation exposure or toxicity, lethal or mucositis effects resulting from treatment with chemotherapy to the subject or subject's intestine Use according to any of claims 13 to 16, wherein   17. Use according to any of claims 13 to 16, wherein the inhibitor is administered to a subject or the subject's intestine as a treatment for colitis, ulcerative colitis, or inflammatory bowel disease.   17. The inhibitor according to any one of claims 13 to 16, wherein the inhibitor is administered to a subject to increase liver regeneration after liver surgery, after living donor liver, after liver transplantation, or after toxin-induced liver damage. Use of.   17. Use according to any of claims 13 to 16, wherein the inhibitor is administered to a subject to promote recovery from or resistance to liver toxins comprising acetaminophen and related compounds.   17. Use according to any of claims 13 to 16, wherein the inhibitor is administered to a subject to treat erectile dysfunction.   17. Use according to any of claims 13 to 16, wherein the inhibitor is administered to inhibit at least one of the growth, proliferation or metastasis of a cancer expressing 15-PGDH.   A method of treating a subject in need of cell therapy, comprising a preparation comprising human hematopoietic stem cells administered to said subject with a therapeutically effective amount of a 15-PGDH inhibitor according to claim 1-12. A method comprising administering a therapeutic composition comprising / or human hematopoietic stem cells and a 15-PGDH inhibitor according to claims 1-12.   Further comprising administering to the subject receiving human hematopoietic stem cells and / or receiving said preparation and / or said therapeutic composition a 15-PGDH inhibitor according to claims 1-12. 128. The method according to 128.   The subject is acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), juvenile myelomonocytic leukemia, Hodgkin lymphoma, non-Hodgkin Lymphoma, multiple myeloma, severe aplastic anemia, Fanconi anemia, paroxysmal nocturnal hemoglobinuria (PNH), erythroblastic fistula, a megakaryocyte / congenital thrombocytopenia, severe combined immunodeficiency syndrome (SCID) , Wiscott-Aldrich syndrome, severe β thalassemia, sickle cell disease, Hurler syndrome, adrenoleukodystrophy, metachromatic leukodystrophy, myelodysplasia, refractory anemia, chronic myelomonocytic leukemia, primary bone marrow fiber , Familial erythrocyte phagocytic lymphohistiocytosis, solid tumor, chronic granulomatous disease, mucopolysaccharidosis, or diamond black Having § emissions anemia The method of claim 71.   15. A method of treating a subject having at least one symptom associated with ischemic tissue or tissue damaged by ischemia, wherein the subject has a therapeutically effective amount of 15- Administering a preparation comprising human hematopoietic stem cells to which a PGDH inhibitor has been administered and / or a therapeutic composition comprising human hematopoietic stem cells and the 15-PGDH inhibitor of claim 1-12.   75. The method of claim 74, wherein the ischemia is associated with at least one of the following: acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusion Arteriosclerosis, articular cartilage defect, aseptic systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, fracture, fracture, brain edema, cerebral hypoperfusion, Buerger disease, burn, cancer, cardiovascular disease, cartilage Injury, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic infection, chronic mesenteric ischemia, lameness, congestive heart failure, connective tissue injury, contusion, coronary artery disease (CAD), severe Ischemic limb (CLI), Crohn's disease, deep vein thrombosis, deep wound, delayed ulcer healing, delayed wound healing, diabetes (type I and type II), diabetic neuropathy, diabetes-induced ischemia, disseminated blood vessel Inside Solid (DIC), embolic cerebral ischemia, graft-versus-host disease, hereditary hemorrhagic telangiectasia ischemic vascular disease, hyperoxia injury, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injury Tendon, intermittent claudication, intestinal ischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic renal disease, ischemic vascular disease, ischemic-reperfusion injury, Laceration, left main coronary artery lesion, ischemic limb, lower limb ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease, peripheral arterial disease (PAD), peripheral arterial disease Peripheral ischemia, peripheral neuropathy, peripheral vascular disease, precancer, pulmonary edema, pulmonary embolism, remodeling disorder, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcer, solid organ transplantation, spinal cord injury, Stroke, subchondral bone cyst, thrombosis, thrombotic cerebral ischemia, tissue ischemia, transient Cerebral ischemic attack (TIA), traumatic brain injury, ulcerative colitis, vascular diseases of the kidney, vascular inflammatory states, von Hippel-Lindau syndrome, and tissue or wound against organ.   A method for increasing neutrophils in a subject in need thereof, comprising administering to the subject the 15-PGDH inhibitor according to claim 1-12.   77. The method of claim 76, further comprising administering a hematopoietic cytokine in combination with a 15-PGDH inhibitor.   A method of increasing and / or mobilizing peripheral blood hematopoietic stem cells in a subject in need thereof, comprising administering to the subject a 15-PGDH inhibitor according to claim 1-12.   79. The method of claim 78, further comprising administering G-CSF in combination with a 15-PGDH inhibitor.   79. The method of claim 78, further comprising administering a hematopoietic cytokine in combination with a 15-PGDH inhibitor.   79. The method of claim 78, further comprising administering plerixafor in combination with a 15-PGDH inhibitor.   82. The method of any of claims 78-81, wherein increasing and / or mobilizing peripheral blood hematopoietic stem cells is used in hematopoietic stem cell transplantation.   A method for increasing the number of hematopoietic stem cells in blood or bone marrow, which comprises administering to the blood or bone marrow of a subject the 15-PGDH inhibitor according to claim 1-12.   84. The method of claim 83, further comprising administering G-CSF in combination with a 15-PGDH inhibitor.   84. The method of claim 83, further comprising administering a hematopoietic cytokine in combination with a 15-PGDH inhibitor.   84. The method of claim 83, further comprising administering plerixafor in combination with a 15-PGDH inhibitor.   A method of treating or preventing a disease, disorder or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a 15-PGDH inhibitor according to claims 1-12.   Said fibrotic disease, disorder or condition can be, in whole or in part, overproduction of fibrous material, eg, overproduction of fibrotic material within the extracellular matrix, or abnormal matrix-related components of normal tissue elements 88. The method of claim 87, characterized by replacement by non-functional and / or excessive accumulation.   Said fibrotic disease, disorder or condition is systemic sclerosis, multifocal fibrosis, renal systemic fibrosis, scleroderma, scleroderma graft-versus-host disease, renal fibrosis, glomerulosclerosis Renal tubulointerstitial fibrosis, progressive or diabetic nephropathy, cardiac fibrosis, pulmonary fibrosis, glomerulosclerosis pulmonary fibrosis, idiopathic pulmonary fibrosis, silicosis, asbestosis , Interstitial lung disease, interstitial fibrosis lung disease, chemotherapy / radiation-induced lung fibrosis, oral fibrosis, endocardial myocardial fibrosis, deltoid fibrosis, pancreatitis, inflammatory bowel disease, Crohn's disease, Nodular fasciitis, eosinophilic fasciitis, general fibrosis syndrome characterized by replacement of normal muscle tissue with fibrous tissue in various degrees, retroperitoneal fibrosis, liver fibrosis, cirrhosis, Chronic renal failure; myelofibrosis, bone marrow Fibrosis, drug-induced ergot poisoning, glioblastoma, sporadic glioblastoma, myeloid leukemia, acute myeloid leukemia, myelodysplastic syndrome, myeloproliferative syndrome in Li-Fraumeni syndrome 88) The method of claim 87, selected from the group consisting of gynecological cancer, Kaposi's sarcoma, leprosy, collagen colitis, acute fibrosis, and organ-specific fibrosis.   90. The method of claim 87, wherein the fibrotic disease, disorder or condition comprises pulmonary fibrosis.   The pulmonary fibrosis is pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, sarcoidosis, cystic fibrosis, familial pulmonary fibrosis, silicosis, asbestosis, Coal miner pneumoconiosis, carbon pneumoconiosis, hypersensitivity pneumonia, pulmonary fibrosis caused by inhalation of inorganic dust, pulmonary fibrosis caused by infectious agents, pulmonary fibers caused by inhalation of harmful gases, aerosols, chemical dust, fume or vapor 94. The method of claim 90, wherein the method is selected from the group consisting of symptom, drug-induced interstitial lung disease, or pulmonary hypertension, and combinations thereof.   92. The method of claim 91, wherein the pulmonary fibrosis is cystic fibrosis.   90. The method of claim 87, wherein the fibrotic disease, disorder or condition comprises renal fibrosis.   90. The method of claim 87, wherein the fibrotic disease, disorder or condition comprises liver fibrosis.   Said liver fibrosis is chronic liver disease, virus-induced cirrhosis, hepatitis B virus infection, hepatitis C virus infection, hepatitis D virus infection, schistosomiasis, primary biliary cirrhosis, alcoholic liver disease or non-alcohol Steatohepatitis (NASH), NASH-related cirrhosis obesity, diabetes, protein nutrition disorders, coronary artery disease, autoimmune hepatitis, cystic fibrosis, α1 antitrypsin deficiency, primary biliary cirrhosis, drug response and toxins 96. The method of claim 95, resulting from exposure, or a combination thereof.   90. The method of claim 87, wherein the fibrotic disease, disorder or condition comprises cardiac fibrosis.   90. The method of claim 87, wherein the fibrotic disease, disorder or condition is systemic sclerosis.   90. The method of claim 87, wherein the fibrotic disease, disorder or condition is caused by post-surgical adhesion formation.   The 15-PGDH inhibitor is administered in an amount effective to reduce or inhibit collagen deposition, inflammatory cytokine expression, and / or inflammatory cell infiltration in the tissue or organ of the subject to be treated. 90. The method according to item 87.